TW201920187A - Novel 5h-pyrrolo[2,3-d]pyrimidin-6(7h)-one derivative - Google Patents

Abstract

The present invention provides a novel compound exhibiting an inhibitory activity against at least one kinase selected from the group consisting of Akt kinase, Rsk kinase and S6K kinase and/or a cell proliferation inhibiting effect. Furthermore, based on the inhibitory activity, the present invention provides a medicine useful for prophylaxis and/or treatment of diseases associated with at least one kinase selected from the group consisting of Akt kinase, Rsk kinase and S6K kinase, particularly cancer. The compound of the present invention or a salt thereof is represented by formula (I), in which R1 represents a 4- to 6-membered monocyclic unsaturated heterocyclic group having 1 to 3 heteroatoms selected from N, S and O and being able to have a substituent; R2 represents a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group; R3, R4 and R5 may be the same or different and represent a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group, or R3 and R4 together with a nitrogen atom to which they are attached form a 4- to 6-membered monocyclic saturated heterocyclic group having 1 to 3 heteroatoms selected from N, S and O and each R5 may be the same or different and is a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group, or R4 and R5 together with a nitrogen atom to which they are attached and the adjacent carbon atoms form a 4- to 6-membered monocyclic saturated heterocyclic group having 1 to 3 heteroatoms selected from N, S and O and each R3 may be the same or different and represents a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group; R6 represents a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group; R7 and R8 may be the same or different and represent a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group, or R7 and R8 together with a carbon atom to which they are attached form a C3-C10 cycloalkyl group; X1 and X2 may be the same or different and represent N or CR9, wherein R9 represents a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group; and X3 represents N or CH when the broken line (---) represents a single bond, and represents C when the broken line represents a double bond, wherein X2 represents N when X1 represents CR9.

Description

Novel 5H-pyrrolo [2, fluorene 3-d] pyrimidin-6 (7H) -one derivative

The present invention relates to a novel 5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one derivative, which is an inhibitor of at least one selected from the group consisting of Akt kinase, Rsk kinase and S6K kinase. , A pharmaceutical composition for treating a disease associated with at least one selected from the group consisting of Akt kinase, Rsk kinase and S6K kinase, and an antitumor agent.

Akt kinase (hereinafter referred to as "Akt") is a serine / threonine kinase also called PKB, and has a central role in the survival, proliferation, and metabolism of cells (Non-Patent Document 1).
The abnormal activation of Akt or the mutation of the Akt gene has been confirmed in various types of cancer, which strongly suggests that Akt is related to the occurrence, maintenance, and physical performance of cancer (Non-Patent Documents 2 and 3).
At present, the industry has developed several inhibitors targeting Akt and has reported on its antitumor effect. However, these inhibitors do not exert sufficient anti-tumor effects as a single agent in non-clinical models, and cannot obtain strong cell-killing effects at low concentrations or strong anti-tumor effects in vivo (non-patent literature) 4, 5). Moreover, the clinical effects of these inhibitors have not been confirmed.
Furthermore, according to reports so far, cancer species exhibiting certain effects with Akt inhibitors are limited to cells or models of breast cancer, prostate cancer, glioma, and the like (Non-Patent Documents 4 and 6). For example, colorectal cancer has shown strong results.
A serine / threonine kinase having a molecular weight of 90 kDa that can phosphorylate 40S ribosomal protein S6 is referred to as Rsk kinase or p90Rsk kinase (hereinafter referred to as "Rsk"). It has been reported that Rsk exists downstream of the Ras-Raf-MAPK signal cascade. It is an important signal transmission molecule with functions of controlling cell proliferation, survival, metabolism and motility, and has various functions required for cancer cell proliferation. (Non-Patent Document 7).
A number of compounds exhibiting inhibitory activity on Rsk have been reported (Non-Patent Documents 7, 8, 9). But its antitumor effect is limited. So far, as a cancer in which Rsk inhibitors have shown a certain effect in non-clinical studies, lung cancer, breast cancer, thyroid cancer, prostate cancer, etc. have been reported, but there are no Rsk inhibitors in the clinical development stage.
S6K kinase (hereinafter referred to as "S6K") is a serine / threonine kinase necessary for the phosphorylation control of 40S ribosomal protein S6, as well as Rsk. It is thought that S6K is controlled by being stimulated by growth factors such as insulin-like growth factors via the PI3K / mTOR signal pathway, and various types of cancer (hyperplasia, survival, invasion, metastasis, etc.) Functional molecule phosphorylation (Non-Patent Document 10). In addition, there have been reports that S6K is generally high in tumors, and S6K inhibition is expected to show antitumor effects.
In recent years, compounds having selective inhibitory activity on S6K have been reported, but in clinical trials, even MTD (Maximum Tolerated Dose) doses have not worked (Non-Patent Document 11).
In addition, as piperidine derivatives having Akt, Rsk, and S6K inhibitory activity, compounds described in Patent Documents 1 and 2 have been reported, but their antitumor effects are not sufficient.
Therefore, in the field of cancer treatment, it is still desired to develop a serine / threonine kinase inhibitor that exerts a strong antitumor effect as a single agent and is effective against a wide range of cancer species.
[Prior technical literature]
[Patent Literature]
Patent Document 1: International Publication No. WO2005 / 117909 Patent Document 2: International Publication No. WO2010 / 056563
[Non-patent literature]
Non-Patent Document 1: J Cell Sci. 2005; 118 (Pt 24): 5675-8.
Non-Patent Document 2: Curr Cancer Drug Targets. 2008; 8 (1): 27-36.
Non-Patent Document 3: Nature. 2007; 448 (7152): 439-44.
Non-Patent Document 4: Mol Cancer Ther. 2005; 4 (6): 977-86.
Non-Patent Document 5: Mol Cancer Ther. 2010; 9 (7): 1956-67.
Non-Patent Document 6: Cancer Res. 2008; 68 (7): 2366-74.
Non-Patent Document 7: Biochem J. 2012; 441 (2): 553-69.
Non-Patent Document 8: Mol Cancer Res. 2014; 12 (5): 803-12.
Non-Patent Document 9: Mol Cancer Ther. 2016; 15 (11): 2598-2608.
Non-Patent Document 10: Int J Biochem Cell Biol. 2011; 43 (1): 47-59.
Non-Patent Document 11: Eur J Cancer. 2014; 50 (5): 867-75.

[Problems to be solved by the invention]
The object of the present invention is to provide a novel 5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one derivative for at least one inhibitor selected from the group consisting of Akt, Rsk and S6K, A pharmaceutical composition or an antitumor agent for treating a disease associated with at least one selected from the group consisting of Akt, Rsk and S6K.
[Technical means to solve the problem]
In order to solve the above-mentioned problems, the present inventors have made diligent researches and found that 5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one is used as the basic structure, and piper A compound group having 6 members of a nitrogen-containing unsaturated heterocyclic ring and the unsaturated heterocyclic ring having a specific substituent has an excellent inhibitory activity against at least one selected from the group consisting of Akt, Rsk, and S6K, And / or cancer cell proliferation inhibitory effect, and / or is useful as a medicine for treating various diseases (especially cancer) related to at least one selected from the group consisting of Akt, Rsk and S6K, thereby completing the present invention.
The present invention includes the following.
[1] A compound or a salt thereof represented by the following formula (I),
[Chemical 1]



[Where,
R ₁ is a monocyclic unsaturated heterocyclic group having 4 to 6 members having 1 to 3 heteroatoms selected from N, S, and O, which may have a substituent;
R ₂ is a hydrogen atom, a halogen atom, a hydroxyl group, an amine group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, or a C3-C6 cycloalkane base;
R ₃ , R ₄ and R _{5 are the} same or different and are a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group or a C3-C6 cycloalkyl group, or the nitrogen to which R ₃ and R ₄ are bonded The atoms together form a monocyclic saturated heterocycle having 4 to 6 members of 1 to 3 heteroatoms selected from N, S, and O, and R ₅ is a hydrogen atom, a C1-C6 alkyl group, and a C1-C6 haloalkane Or C3-C6 cycloalkyl, or R ₄ and R ₅ together with these bonded nitrogen atoms and adjacent carbon atoms to form 4 to 4 having 1 to 3 heteroatoms selected from N, S, and O 6-membered monocyclic saturated heterocyclic ring, and R ₃ is a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group;
R ₆ is a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group;
R ₇ and R _{8 are the} same or different, and are a hydrogen atom, a halogen atom, a hydroxyl group, an amine group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, and a C2-C6 alkyne Or C3-C6 cycloalkyl, or R ₇ and R ₈ together with the carbon atoms to which they are bonded form a C3-C10 cycloalkyl;
X ₁ and X _{2 are the} same or different and are N or CR ₉ , and R ₉ is a hydrogen atom, a halogen atom, a hydroxyl group, an amine group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, and a C2- C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl;
X ₃ in the dotted line ( ) Is N or CH when a single bond is used, and C when a dotted line is a double bond. Where at least one of X ₁ and X ₂ is N]
[2] The compound or a salt thereof according to [1], wherein R ₁ may have a member selected from a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, and a C3-C10 cycloalkyl group A monocyclic unsaturated heterocyclic group having 4 to 6 members of 1 to 3 substituents having 1 to 3 heteroatoms selected from N, S, and O.
[3] The compound or a salt thereof according to [1] or [2], wherein R ₂ is a hydrogen atom or a halogen atom, R ₆ is a hydrogen atom, R ₇ is a C1-C6 alkyl group, and R ₈ is a hydrogen atom or C1- C6 alkyl, X ₁ is N or CR ₉ , R ₉ is a hydrogen atom or a halogen atom, and X ₂ is N or CH.
[4] The compound or the salt thereof according to any one of [1] to [3], wherein R ₁ may have a member selected from a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, and a C1-C6 alkoxy group Furanyl, thienyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridyl, or pyrazolyl among 1 to 3 substituents of C3-C10 cycloalkyl.
[5] The compound or the salt thereof according to any one of [1] to [4], wherein R ₃ , R ₄ and R _{5 are the} same or different, are a hydrogen atom or a C1-C6 alkyl group, or R ₃ and R ₄ Together with these bonded nitrogen atoms to form a monocyclic saturated heterocyclic ring having 4 to 6 members with 1 nitrogen atom, and R ₅ is a hydrogen atom or a C1-C6 alkyl group, or R ₄ and R ₅ and the The bonded nitrogen atom and the adjacent carbon atom together form a monocyclic saturated heterocyclic ring having 4 to 6 members of one nitrogen atom, and R ₃ is a hydrogen atom or a C1-C6 alkyl group.
[6] The compound or the salt thereof according to any one of [1] to [5], wherein R ₁ is a pyridyl group having a halogen atom or a C1-C6 alkoxy group, a C1-C6 alkyl group, and a C1-C6 halogen Alkyl pyrazolyl, oxadiazolyl with C1-C6 haloalkyl, or unsubstituted furyl, or thiazolyl,
R ₂ , R ₅ and R ₆ are hydrogen atoms,
R ₃ is a hydrogen atom, and R ₄ is a C1-C6 alkyl group, or R ₃ and R ₄ together with these bonded nitrogen atoms form a monocyclic saturated heterocyclic ring having 4 to 6 members having one nitrogen atom ,
R ₇ is a C1-C6 alkyl group, R ₈ is a hydrogen atom or a C1-C6 alkyl group,
X ₁ and X _{2 are} different from each other and are N or CH,
Dotted line ( ) Is a single bond and X ₃ is CH.
[7] The compound or a salt thereof according to [6], wherein R ₁ is a pyrazolyl group having a C1-C6 alkyl group and a C1-C6 haloalkyl group, or a oxadiazolyl group having a C1-C6 haloalkyl group.
[8] The compound or the salt thereof according to any one of [1] to [7], wherein the compound is one selected from the following group of compounds:
4- (4- (6- (5- (difluoromethyl) -1,3,4-fluorenediazol-2-yl) -3-((2- (pyrrolidin-1-yl) ethyl) Amine) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one;
4- (4- (3-((2- (third-butylamino) ethyl) amino) -6- (5- (trifluoromethyl) -1,3,4-fluorenediazole-2 -Yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one; and
4- (4- (3-((2- (third-butylamino) ethyl) amino) -6- (5- (difluoromethyl) -1,2,4-fluorenediazole-3 -Yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one.
[9] An Akt inhibitor, comprising the compound according to any one of [1] to [8] or a salt thereof as an active ingredient.
[10] An Rsk inhibitor using the compound or a salt thereof according to any one of [1] to [8] as an active ingredient.
[11] An S6K inhibitor comprising the compound or a salt thereof according to any one of [1] to [8] as an active ingredient.
[12] An inhibitor for at least two selected from the group consisting of Akt, Rsk, and S6K, which uses the compound or a salt thereof according to any one of [1] to [8] as an active ingredient.
[13] An inhibitor of Akt, Rsk, and S6K, which uses the compound or a salt thereof according to any one of [1] to [8] as an active ingredient.
[14] A pharmaceutical composition for treating Akt-related diseases, which contains the compound according to any one of [1] to [8] or a salt thereof as an active ingredient.
[15] A pharmaceutical composition for treating a disease related to Rsk, which contains the compound according to any one of [1] to [8] or a salt thereof as an active ingredient.
[16] A pharmaceutical composition for treating S6K-related diseases, which contains the compound according to any one of [1] to [8] or a salt thereof as an active ingredient.
[17] A pharmaceutical composition for treating diseases related to at least two selected from the group consisting of Akt, Rsk and S6K, which contains the compound according to any one of [1] to [8] or a compound thereof Salt as an active ingredient.
[18] A pharmaceutical composition for treating diseases related to Akt, Rsk, and S6K, which contains the compound according to any one of [1] to [8] or a salt thereof as an active ingredient.
[19] An antitumor agent comprising the compound according to any one of [1] to [8] or a salt thereof as an active ingredient.
The present invention further includes the following.
[20-1] The compound or a salt thereof according to any one of [1] to [8], which is used to inhibit Akt.
[20-2] The compound or a salt thereof according to any one of [1] to [8], which is used to inhibit Rsk.
[20-3] The compound or a salt thereof according to any one of [1] to [8], which is used to inhibit S6K.
[20-4] The compound or a salt thereof according to any one of [1] to [8], for inhibiting at least two kinds selected from the group consisting of Akt, Rsk, and S6K.
[20-5] The compound or a salt thereof according to any one of [1] to [8], which is used to inhibit Akt, Rsk, and S6K.
[21-1] The compound or a salt thereof according to any one of [1] to [8], which is used for treating an Akt-related disease.
[21-2] The compound or a salt thereof according to any one of [1] to [8], which is used for treating a disease related to Rsk.
[21-3] The compound or a salt thereof according to any one of [1] to [8], which is used for treating a disease related to S6K.
[21-4] The compound or a salt thereof according to any one of [1] to [8], which is used for treating a disease associated with at least two selected from the group consisting of Akt, Rsk, and S6K.
[21-5] The compound or a salt thereof according to any one of [1] to [8], which is used for treating diseases related to Akt, Rsk, and S6K.
[22] The compound or a salt thereof according to any one of [1] to [8], which is used for treating a tumor.
[23-1] Use of a compound or a salt thereof according to any one of [1] to [8] for inhibiting Akt.
[23-2] Use of a compound or a salt thereof according to any one of [1] to [8] for inhibiting Rsk.
[23-3] Use of a compound or a salt thereof according to any one of [1] to [8] for inhibiting S6K.
[23-4] The use of a compound or a salt thereof according to any one of [1] to [8] for inhibiting at least two kinds selected from the group consisting of Akt, Rsk, and S6K.
[23-5] Use of a compound or a salt thereof according to any one of [1] to [8] for inhibiting Akt, Rsk, and S6K.
[24-1] Use of a compound or a salt thereof according to any one of [1] to [8], for the treatment of Akt-related diseases.
[24-2] Use of a compound or a salt thereof according to any one of [1] to [8], for treating a disease related to Rsk.
[24-3] Use of a compound or a salt thereof according to any one of [1] to [8], for the treatment of a disease related to S6K.
[24-4] Use of a compound or a salt thereof according to any one of [1] to [8] for the treatment of diseases associated with at least two selected from the group consisting of Akt, Rsk and S6K .
[24-5] Use of a compound or a salt thereof according to any one of [1] to [8], for treating diseases related to Akt, Rsk, and S6K.
[25] Use of a compound or a salt thereof according to any one of [1] to [8], for treating a tumor.
[26-1] Use of a compound or a salt thereof according to any one of [1] to [8], for producing a medicine for inhibiting Akt.
[26-2] Use of a compound or a salt thereof according to any one of [1] to [8], for producing a medicine for inhibiting Rsk.
[26-3] Use of a compound or a salt thereof according to any one of [1] to [8], for producing a medicine for inhibiting S6K.
[26-4] Use of a compound or a salt thereof according to any one of [1] to [8] for producing a compound for inhibiting at least two selected from the group consisting of Akt, Rsk, and S6K medicine.
[26-5] Use of a compound or a salt thereof according to any one of [1] to [8], for producing a medicine for inhibiting Akt, Rsk, and S6K.
[27-1] Use of a compound or a salt thereof according to any one of [1] to [8] for the manufacture of a medicament for the treatment of diseases related to Akt.
[27-2] Use of a compound or a salt thereof according to any one of [1] to [8], for the manufacture of a medicament for treating a disease related to Rsk.
[27-3] Use of a compound or a salt thereof according to any one of [1] to [8], for producing a medicine for treating S6K-related diseases.
[27-4] Use of a compound or a salt thereof according to any one of [1] to [8] for the manufacture of at least two kinds selected from the group consisting of Akt, Rsk, and S6K for treatment Medicine for related diseases.
[27-5] Use of a compound or a salt thereof according to any one of [1] to [8], for the manufacture of a medicine for treating diseases related to Akt, Rsk, and S6K.
[28] Use of a compound or a salt thereof according to any one of [1] to [8], for producing a medicine for treating tumors.
[29-1] A method for inhibiting Akt, which comprises administering to a patient in need thereof an effective amount of a compound such as any one of [1] to [8] or a salt thereof.
[29-2] A method for inhibiting Rsk, comprising administering to a patient in need thereof an effective amount of a compound such as any one of [1] to [8] or a salt thereof.
[29-3] A method for inhibiting S6K, which comprises administering to a patient in need thereof an effective amount of a compound such as any one of [1] to [8] or a salt thereof.
[29-4] A method for inhibiting at least two selected from the group consisting of Akt, Rsk, and S6K, which comprises administering an effective amount of any one of [1] to [8] to a patient in need thereof Or a salt thereof.
[29-5] A method for inhibiting Akt, Rsk, and S6K, which comprises administering to a patient in need thereof an effective amount of a compound such as any one of [1] to [8] or a salt thereof.
[30-1] A method for treating an Akt-related disease, which comprises administering to a patient in need thereof an effective amount of a compound such as any one of [1] to [8] or a salt thereof.
[30-2] A method for treating a disease associated with Rsk, which comprises administering to a patient in need thereof an effective amount of a compound such as any one of [1] to [8] or a salt thereof.
[30-3] A method for treating a disease related to S6K, which comprises administering to a patient in need thereof an effective amount of a compound such as any one of [1] to [8] or a salt thereof.
[30-4] A method for treating a disease associated with at least two selected from the group consisting of Akt, Rsk, and S6K, which comprises administering an effective amount such as [1] to [8] to a patient in need thereof Or a salt thereof.
[30-5] A method for treating diseases related to Akt, Rsk, and S6K, which comprises administering to a patient in need thereof an effective amount of a compound such as any one of [1] to [8] or a salt thereof.
[31] A method for treating a tumor, comprising administering to a patient in need thereof an effective amount of a compound such as any one of [1] to [8] or a salt thereof.
This specification contains the contents of Japanese Patent Application No. 2016-101599, which forms the basis of the priority of the present application.
[Effect of the invention]
According to the present invention, there is provided a novel 5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one derivative for at least one inhibitor selected from the group consisting of Akt, Rsk and S6K. A pharmaceutical composition for treating a disease associated with at least one selected from the group consisting of Akt, Rsk and S6K, or an antitumor agent.
It is understood that in one embodiment, the compound of the present invention or a salt thereof has excellent inhibitory activity on at least one selected from the group consisting of Akt, Rsk, and S6K, and exhibits a proliferation inhibitory effect on cancer cell lines. Therefore, the compound of the present invention or a salt thereof is useful as a preventive and / or therapeutic agent for diseases related to at least one selected from the group consisting of Akt, Rsk and S6K, such as cancer.

The compound represented by the above formula (I) of the present invention is characterized in that 5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one is used as the basic structure, It has a 6-membered nitrogen-containing unsaturated heterocyclic ring, and the unsaturated heterocyclic ring has a specific substituent. This compound is a novel compound which is not described in each of the aforementioned prior art documents and the like.
In the present specification, examples of the "substituent" include a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C10 cycloalkyl group, and a C2-C6 alkenyl group. , C2-C6 alkynyl, C1-C6 alkoxy, amine, mono- or dialkylamino, fluorenyl, carboxyl, alkoxycarbonyl, carbamoyl, having a group selected from N, S, and O 4 to 10-membered saturated heterocyclic groups of 1 to 4 heteroatoms or 4 to 10-membered unsaturated heterocyclic groups, C6-C14 aromatic hydrocarbon groups, etc. When the above substituents are present, the number is typically Say 1-3.
In the present specification, specific examples of the "halogen atom" include a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom, preferably a chlorine atom and a fluorine atom, and particularly preferably a fluorine atom.
In the present specification, the "C1-C6 alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, and isopropyl. , N-butyl, isobutyl, second butyl, third butyl, pentyl, hexyl, etc., preferably a linear alkyl group having 1 to 4 carbon atoms or a branched chain having 3 to 4 carbon atoms The alkyl group is more preferably a methyl group, an isopropyl group, or a third butyl group.
In the present specification, the "C2-C6 alkenyl group" means a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms including at least one carbon-carbon double bond. Specific examples include vinyl and allyl groups. Group, methylvinyl, propenyl, butenyl, pentenyl, hexenyl, etc., preferably a straight or branched hydrocarbon group having 2 to 4 carbon atoms containing at least one carbon-carbon double bond .
In the present specification, the "C2-C6 alkynyl group" means a straight-chain or branched hydrocarbon group having 2 to 6 carbon atoms containing at least one carbon-carbon triple bond. Specifically, ethynyl, 2- Propynyl and the like are preferably straight-chain or branched hydrocarbon groups having 2 to 4 carbon atoms and containing at least one carbon-carbon triple bond.
In the present specification, the "C1-C6 haloalkyl group" means that one to all hydrogen atoms in a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms are substituted with the above-mentioned halogen atom group, and specifically, Examples include: monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 2 1,2-difluoroethyl, 2,2,2-trifluoroethyl, etc., preferably 1 to 3 hydrogen atoms in a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms are substituted Is a base of the above-mentioned halogen atom, and more preferably difluoromethyl or trifluoromethyl.
In the present specification, the "C1-C6 alkoxy group" means an oxygen group having a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and specific examples include a methoxy group and an ethoxy group. Group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, third butoxy group, etc., preferably a linear or branched chain saturated with 1 to 4 carbon atoms. The alkoxy group is more preferably a methoxy group.
In the present specification, the "C3-C10 cycloalkyl group" means a monocyclic or polycyclic saturated hydrocarbon group having 3 to 10 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclodecyl, and the like are preferably monocyclic saturated hydrocarbon groups having 3 to 6 carbon atoms, and more preferably cyclopropyl.
In the present specification, the "4- to 10-membered saturated heterocyclic group" means a 4- to 10-membered monocyclic or polycyclic fully saturated heterocyclic group, and specifically, azacyclobutyl, Pyrrolidinyl, piperidinyl, piperidinyl, hexamethyleneiminyl, phosphono, thiophosphonyl, homopiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, etc., preferably selected from among N, S and O A monocyclic or polycyclic fully saturated heterocyclic group having 1 to 4 heteroatoms and 4 to 10 members.
In the present specification, the "4- to 6-membered monocyclic saturated heterocyclic group" means a 4- to 6-membered monocyclic fully saturated heterocyclic group. Specifically, examples include azetidinyl and pyrrolidine Group, piperidinyl, piperidinyl, hexamethyleneimino, phosphono, thioline, etc., preferably 4 to 6 members having 1 to 4 heteroatoms selected from N, S and O A monocyclic fully saturated heterocyclic group, more preferably a monocyclic fully saturated heterocyclic group having 5 to 6 members of 1 to 3 heteroatoms selected from N, S, and O, and most preferably pyrrolidine base.
In the present specification, the "4- to 10-membered unsaturated heterocyclic group" means a 4- to 10-membered monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group, and specifically, it is completely unsaturated. Examples of unsaturated heterocyclic groups include: pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, and thiazolyl , Isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridyl, daphyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzotriazolyl, azaindole Methyl, pyrrolopyridyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, pyrrolopyrimidyl, imidazopyrimidyl, pyrazolopyrimidyl, benzofuranyl, benzooxazolyl , Benzothienyl, benzothiazolyl, quinolinyl, isoquinolyl, quinazolinyl, quinazolinyl, etc. Examples of partially unsaturated unsaturated heterocyclic groups include indolyl, Methylenedioxyphenyl, ethylenedioxyphenyl, dihydrobenzofuranyl and the like. A monocyclic or polycyclic fully unsaturated or partially saturated heterocyclic group having 4 to 10 members of 1 to 4 heteroatoms selected from N, S, and O is preferred.
In the present specification, the "4- to 6-membered monocyclic unsaturated heterocyclic group" means a 4- to 6-membered monocyclic completely unsaturated or partially unsaturated heterocyclic group, and specifically, it is referred to as a completely unsaturated group. Examples of unsaturated heterocyclic groups include: pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, and thiazolyl , Isothiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, daphthyl, etc. Examples of partially unsaturated unsaturated heterocyclic groups include tetradihydrofuryl, dihydropyranyl, dihydrothienyl , Tetrahydropyridyl, dihydrothyranyl and the like. A monocyclic fully unsaturated heterocyclic group having 4 to 6 members of 1 to 4 heteroatoms selected from N, S, and O is preferred, and 1 is selected from N, S, and O. A monocyclic fully unsaturated heterocyclic group of 5 to 6 members of ～ 3 heteroatoms, particularly preferably pyridyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, furan And thienyl.
In the present specification, the "C6-C14 aromatic hydrocarbon group" means a monocyclic or polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms, and specifically, phenyl, naphthyl, tetrahydronaphthyl, Anthracenyl and others.
In formula (I), R₁ It is "a monocyclic unsaturated heterocyclic group having 4 to 6 members having 1 to 3 heteroatoms selected from N, S, and O which may have a substituent".
About R₁ As the "monocyclic unsaturated heterocyclic group having 4 to 6 members having 1 to 3 heteroatoms selected from N, S, and O", the above-mentioned "monocyclic unsaturated heterocyclic group having 4 to 6 members "Ring group" is preferably a monocyclic completely unsaturated heterocyclic group having 5 to 6 members of 1 to 3 heteroatoms selected from N, S and O, and more preferably pyridyl, pyrazolyl, Thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, furyl, thienyl.
"A monocyclic unsaturated heterocyclic group having 4 to 6 members having 1 to 3 heteroatoms selected from N, S and O" may be substituted or unsubstituted. The number of substituents is preferably 1 to 3. Here, as the substituent, the above-mentioned "substituent" may be mentioned, and a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkyl group, and a C3-C10 cycloalkyl group are preferably used. The composition group is selected, and the group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C1-C6 haloalkyl group can be selected more preferably, and a C1-C6 alkyl group is more preferable. And / or C1-C6 haloalkyl.
Preferably, in formula (I), R₁ It has a substituent selected from N, S, and C which may have 1 to 3 substituents selected from a halogen atom, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C10 cycloalkyl. A monocyclic unsaturated heterocyclic group having 4 to 6 members of 1 to 3 heteroatoms in O.
More preferably, in formula (I), R₁ Furanyl, thienyl, thiazole which may have 1 to 3 substituents selected from halogen atom, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C3-C10 cycloalkyl Group, thiadiazolyl, oxazolyl, oxadiazolyl, pyridyl or pyrazolyl.
More preferably, in formula (I), R₁ Pyridyl, pyrazolyl, thiazole having 1 to 3 substituents selected from a halogen atom, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C10 cycloalkyl Radical, oxadiazolyl or thiadiazolyl, or unsubstituted furanyl, thienyl, thiazolyl or oxazolyl.
More preferably, in formula (I), R₁ Is a pyridyl group having a halogen atom or a C1-C6 alkoxy group, a pyrazolyl group having a C1-C6 alkyl group and a C1-C6 haloalkyl group, an amidazolyl group having a C1-C6 haloalkyl group, or unsubstituted Furyl, or thiazolyl.
Especially preferably, in formula (I), R₁ It is a pyrazolyl group having a C1-C6 alkyl group and a C1-C6 haloalkyl group, or an oxadiazolyl group having a C1-C6 haloalkyl group.
In formula (I), R₂ It is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group or a C3-C6 cycloalkyl group.
Preferably, in formula (I), R₂ Is a hydrogen atom, a halogen atom or a C1-C6 alkyl group, more preferably a hydrogen atom or a halogen atom, and even more preferably a hydrogen atom.
In formula (I), R₃ , R₄ And R₅ The same or different, is a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group, or R₃ And R₄ Together with these bonded nitrogen atoms to form a monocyclic saturated heterocyclic ring having 4 to 6 members of 1 to 3 heteroatoms selected from N, S and O, and R₅ Is a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group, or R₄ And R₅ Forms a monocyclic saturated heterocyclic ring having 4 to 6 members with 1 to 3 heteroatoms selected from N, S, and O together with the bonded nitrogen atoms and adjacent carbon atoms, and R₃ It is a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group.
In formula (I), as R₃ And R₄ The "monocyclic saturated heterocyclic ring having 4 to 6 members with 1 to 3 heteroatoms selected from N, S, and O together with these bonded nitrogen atoms" can be mentioned, and the above-mentioned "4 A monocyclic saturated heterocyclic ring having 6 to 6 members "is preferably a monocyclic saturated heterocyclic ring having 4 to 6 members having one nitrogen atom, and particularly preferably a pyrrolidinyl group.
In formula (I), as R₄ And R₅ "Single-ring saturated heterocyclic ring having 4 to 6 members of 1 to 3 heteroatoms selected from N, S, and O together with these bonded nitrogen atoms and adjacent carbon atoms", The above-mentioned "monocyclic saturated heterocyclic ring of 4 to 6 members" may be mentioned, and a monocyclic saturated heterocyclic ring of 4 to 6 members having one nitrogen atom is preferable, and a pyrrolidinyl group is particularly preferable.
Preferably, in formula (I), R₃ , R₄ And R₅ The same or different, is a hydrogen atom or a C1-C6 alkyl group, or R₃ And R₄ Together with these bonded nitrogen atoms to form a monocyclic saturated heterocyclic ring having 4 to 6 members with 1 nitrogen atom, and R₅ Is a hydrogen atom or a C1-C6 alkyl group, or R₄ And R₅ Together with these bonded nitrogen atoms and adjacent carbon atoms to form a monocyclic saturated heterocyclic ring having 4 to 6 members of one nitrogen atom, and R₃ Is a hydrogen atom or a C1-C6 alkyl group.
Especially preferably, in formula (I), R₃ And R₅ Is a hydrogen atom, and R₄ C1-C6 alkyl, or R₃ And R₄ Together with these bonded nitrogen atoms to form a 4- to 6-membered monocyclic saturated heterocyclic ring, and R₅ Is a hydrogen atom.
In formula (I), R₆ It is a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C6 cycloalkyl group.
Preferably, in formula (I), R₆ Is a hydrogen atom or a C1-C6 alkyl group, particularly preferably a hydrogen atom.
In formula (I), R₇ And R₈ The same or different, is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, or a C3-C6 Cycloalkyl, or R₇ And R₈ Together with these bonded carbon atoms, a C3-C10 cycloalkyl group is formed.
Preferably, in formula (I), R₇ And R₈ The same or different, and it is a hydrogen atom or a C1-C6 alkyl group. More preferably, in formula (I), R₇ C1-C6 alkyl, R₈ Is a hydrogen atom or a C1-C6 alkyl group, particularly preferably R₇ Is methyl, R₈ Is a hydrogen atom or a methyl group.
In formula (I), X₁ And X₂ Same or different, N or CR₉ , R₉ It is a hydrogen atom, a halogen atom, a hydroxyl group, an amine group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, or a C3-C6 cycloalkyl group. Where X₁ And X₂ At least one of them is N.
Preferably, in formula (I), X₁ N or CR₉ , R₉ Is a hydrogen atom, a halogen atom or a C1-C6 alkyl group, X₂ Is N or CH (where X₁ And X₂ At least one of them is N). Better to X₁ Is N and X₂ Is CH, or X₁ For CR₉ , R₉ Is a hydrogen atom or a halogen atom, and X₂ Is N. Better to X₁ And X₂ They are different from each other and are N or CH. Especially good for X₁ For N, X₂ Is CH.
In formula (I), X₃ In the dotted line () Is N or CH when a single bond is used, and C when a dotted line is a double bond. Preferably, in formula (I), X₃ In the dotted line () Is CH in the case of a single bond, C in the case of a double bond in the dotted line portion, and particularly preferably the dotted line () Is a single key, X₃ Is CH.
As the compound of the present invention, the following compounds are preferred: In the formula (I), R₁ It has a substituent selected from N, S, and A monocyclic unsaturated heterocyclic group of 4 to 6 members of 1 to 3 heteroatoms in O,
R₂ Is a hydrogen atom or a halogen atom,
R₃ , R₄ And R₅ The same or different, is a hydrogen atom or a C1-C6 alkyl group, or R₃ And R₄ Together with these bonded nitrogen atoms to form a monocyclic saturated heterocyclic ring having 4 to 6 members with 1 nitrogen atom, and R₅ Is a hydrogen atom or a C1-C6 alkyl group, or R₄ And R₅ Together with these bonded nitrogen atoms and adjacent carbon atoms to form a monocyclic saturated heterocyclic ring having 4 to 6 members of one nitrogen atom, and R₃ Is a hydrogen atom or a C1-C6 alkyl group, or R₃ And R₅ Is a hydrogen atom, and R₄ C1-C6 alkyl, or R₃ And R₄ Together with these bonded nitrogen atoms to form a monocyclic saturated heterocyclic ring having 4 to 6 members with 1 nitrogen atom, and R₅ Is a hydrogen atom,
R₆ Is a hydrogen atom,
R₇ C1-C6 alkyl, R₈ Is a hydrogen atom or a C1-C6 alkyl group,
X₁ And X₂ Different from each other, N or CH,
Dotted line () Is a single key, X₃ Is CH;
More preferred are the following compounds: R₁ Furanyl, thienyl, thiazole which may have 1 to 3 substituents selected from halogen atom, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C3-C10 cycloalkyl , Thiadiazolyl, oxazolyl, oxadiazolyl, pyridyl or pyrazolyl,
R₂ And R₆ Is a hydrogen atom,
R₃ , R₄ And R₅ The same or different, is a hydrogen atom or a C1-C6 alkyl group, or R₃ And R₄ Together with these bonded nitrogen atoms to form a monocyclic saturated heterocyclic ring having 4 to 6 members with 1 nitrogen atom, and R₅ Is a hydrogen atom or a C1-C6 alkyl group, or R₄ And R₅ Together with these bonded nitrogen atoms and adjacent carbon atoms to form a monocyclic saturated heterocyclic ring having 4 to 6 members of one nitrogen atom, and R₃ Is a hydrogen atom or a C1-C6 alkyl group, or R₃ And R₅ Is a hydrogen atom, and R₄ C1-C6 alkyl, or R₃ And R₄ Together with these bonded nitrogen atoms to form a monocyclic saturated heterocyclic ring having 4 to 6 members with 1 nitrogen atom, and R₅ Is a hydrogen atom,
R₇ C1-C6 alkyl, R₈ Is a hydrogen atom or a C1-C6 alkyl group,
X₁ And X₂ Different from each other, N or CH,
Dotted line () Is a single key, X₃ Is CH;
More preferred are the compounds: in formula (I), R₁ Is a pyridyl group having a halogen atom or a C1-C6 alkoxy group, a pyrazolyl group having a C1-C6 alkyl group and a C1-C6 haloalkyl group, an oxadiazolyl group having a C1-C6 haloalkyl group, or unsubstituted Furyl, or thiazolyl,
R₂ , R₅ And R₆ Is a hydrogen atom,
R₃ Is a hydrogen atom, and R₄ C1-C6 alkyl, or R₃ And R₄ Together with these bonded nitrogen atoms to form a monocyclic saturated heterocyclic ring having 4 to 6 members of 1 nitrogen atom,
R₇ C1-C6 alkyl, R₈ Is a hydrogen atom or a C1-C6 alkyl group,
X₁ And X₂ Different from each other, N or CH,
Dotted line () Is a single key, X₃ Is CH;
More preferred are the following compounds: R₁ Is a pyrazolyl group having a C1-C6 alkyl group and a C1-C6 haloalkyl group, or an oxadiazolyl group having a C1-C6 haloalkyl group,
R₂ , R₅ And R₆ Is a hydrogen atom,
R₃ Is a hydrogen atom, and R₄ C1-C6 alkyl, or R₃ And R₄ Together with these bonded nitrogen atoms to form a monocyclic saturated heterocyclic ring having 4 to 6 members of 1 nitrogen atom,
R₇ C1-C6 alkyl, R₈ Is a hydrogen atom or a C1-C6 alkyl group,
X₁ And X₂ Different from each other, N or CH,
Dotted line () Is a single key, X₃ Is CH;
Further preferred are the following compounds: R₁ Is a pyrazolyl group having a methyl group and a trifluoromethyl group, or an oxadiazolyl group having a difluoromethyl group,
R₂ , R₅ And R₆ Is a hydrogen atom,
R₃ Is a hydrogen atom, and R₄ Is isopropyl or tertiary butyl, or R₃ And R₄ With these bonded nitrogen atoms to form pyrrolidinyl,
R₇ Is methyl, R₈ Is a hydrogen atom or a methyl group,
X₁ And X₂ Different from each other, N or CH,
Dotted line () Is a single key, X₃ Is CH.
Specific examples of the compound of the present invention include compounds produced in the following examples, but are not limited thereto.
As preferred compounds of the present invention, the following can be exemplified:
4- (4- (5-((2- (third-butylamino) ethyl) amino) -5'-fluoro- [2,3'-bipyridine] -6-yl) piperidine-1 -Yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (1));
4- (4- (2'-fluoro-5-((2- (pyrrolidin-1-yl) ethyl) amino)-[2,4'-bipyridyl] -6-yl) piperidine-1 -Yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (13));
4- (4- (6- (furan-3-yl) -3-((2- (pyrrolidin-1-yl) ethyl) amino) pyridin-2-yl) piperidin-1-yl)- 5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound 14);
4- (4- (5-((2- (isopropylamino) ethyl) amino) -5'-methoxy- [2,3'-bipyridyl] -6-yl) piperidine- 1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (15));
5-methyl-4- (4- (3-((2- (pyrrolidin-1-yl) ethyl) amino) -6- (thiazol-2-yl) pyridin-2-yl) piperidine- 1-yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (24));
4- (5-fluoro-5 '-((2- (pyrrolidin-1-yl) ethyl) amino) -5' ', 6' '-dihydro- [3,2': 6 ', 4 `` -Terpyridine] -1 '' (2''H) -yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (26)) ;
5-methyl-4- (4- (5- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -2-((2- (pyrrolidine-1- ) Ethyl) amino) pyridin-3-yl) piperidin-1-yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (27));
4- (4- (6- (5- (difluoromethyl) -1,3,4-fluorenediazol-2-yl) -3-((2- (pyrrolidin-1-yl) ethyl) Amine) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (30)) ;
4- (4- (3-((2- (third-butylamino) ethyl) amino) -6- (5- (trifluoromethyl) -1,3,4-fluorenediazole-2 -Yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (32)) ;
4- (4- (3-((2- (third-butylamino) ethyl) amino) -6- (5- (difluoromethyl) -1,2,4-fluorenediazole-3 -Yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (41)) ;and
5,5-dimethyl-4- (4- (3-((2- (pyrrolidin-1-yl) ethyl) amino) -6- (3- (trifluoromethyl) -1,2 , 4-fluorenediazol-5-yl) pyridin-2-yl) piperidin-1-yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (44)) .
As more preferable compounds of the present invention, the following may be exemplified:
4- (4- (5-((2- (third-butylamino) ethyl) amino) -5'-fluoro- [2,3'-bipyridine] -6-yl) piperidine-1 -Yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (1));
4- (4- (2'-fluoro-5-((2- (pyrrolidin-1-yl) ethyl) amino)-[2,4'-bipyridyl] -6-yl) piperidine-1 -Yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (13));
4- (4- (6- (furan-3-yl) -3-((2- (pyrrolidin-1-yl) ethyl) amino) pyridin-2-yl) piperidin-1-yl)- 5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound 14);
4- (4- (5-((2- (isopropylamino) ethyl) amino) -5'-methoxy- [2,3'-bipyridyl] -6-yl) piperidine- 1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (15));
4- (4- (6- (5- (difluoromethyl) -1,3,4-fluorenediazol-2-yl) -3-((2- (pyrrolidin-1-yl) ethyl) Amine) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (30)) ;
4- (4- (3-((2- (third-butylamino) ethyl) amino) -6- (5- (trifluoromethyl) -1,3,4-fluorenediazole-2 -Yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (32)) ;
4- (4- (3-((2- (third-butylamino) ethyl) amino) -6- (5- (difluoromethyl) -1,2,4-fluorenediazole-3 -Yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (41)) ;and
5,5-dimethyl-4- (4- (3-((2- (pyrrolidin-1-yl) ethyl) amino) -6- (3- (trifluoromethyl) -1,2 , 4-fluorenediazole-5-yl) pyridin-2-yl) piperidin-1-yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (44)) .
As particularly preferred compounds of the present invention, from the viewpoint of oral absorption and hERG test (cardiotoxicity), the following can be exemplified:
4- (4- (6- (5- (difluoromethyl) -1,3,4-fluorenediazol-2-yl) -3-((2- (pyrrolidin-1-yl) ethyl) Amine) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (30)) ;
4- (4- (3-((2- (third-butylamino) ethyl) amino) -6- (5- (trifluoromethyl) -1,3,4-fluorenediazole-2 -Yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (32)) ;and
4- (4- (3-((2- (third-butylamino) ethyl) amino) -6- (5- (difluoromethyl) -1,2,4-fluorenediazole-3 -Yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (41)) .
Next, the manufacturing method of the compound of this invention is demonstrated.
The compound represented by the formula (I) of the present invention can be produced, for example, by the following production method or the method shown in Examples. The production method of the compound represented by the formula (I) of the present invention is not limited to these reaction examples. The product obtained in each step can be isolated and purified by known separation and purification methods, such as concentration, reduced pressure concentration, crystallization, solvent extraction, reprecipitation, chromatography, etc., or can be supplied to the next step without isolation purification. step.
[Chemical 2]


[Where, R₉ For hydrogen atom or PG₁ . R₇ And R₈ Synonymous with the above. X_3a In the dotted line () Is NPG when single bond₂ , NH or CHR₁₀ , CR in the case where the dotted line is a double bond₁₀ . R₁₀ B (OR₁₁ )₂ , Hydroxy, halo, or formula (VI)

[Chemical 3]



(Where, X₁ , X₂ , R₂ Synonymous with the above. R_1a For hydrogen atom, halo, cyano, CO₂ R₁₁ , Or with R₁ Synonymous. R₁₂ Is amine, 2-hydroxyethyl, or formula (VII)
[Chemical 4]


(Where, R₃ , R₄ , R₅ And R₆ (Synonymous with above)
(Represented substituents)
The substituents indicated. R₁₁ Is a hydrogen atom or a substituted lower alkyl group (2 R₁₁ It may form a ring together with the bonded oxygen atom (the ring may have a substituent)). PG₁ And PG₂ (Indicating protecting group)
(Step 1) This step is a step of treating a compound represented by the formula (II) with a base and an alkylating agent, and producing a compound represented by the formula (III) by an alkylation reaction.
Examples of the base used in this step include triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium third butyrate, sodium third butyrate, and sodium methoxide. , Sodium ethoxide, lithium bis (trimethylsilane) amine, sodium bis (trimethylsilane) amine, potassium bis (trimethylsilane) amine, lithium diisopropylamidamine, butyl lithium, etc. Base, or inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride.
As the alkylating agent used in this step, as long as it is capable of introducing R₇ And R₈ It is not particularly limited, and examples thereof include methyl iodide, ethyl iodide, 1,2-dibromoethane, 1,3-dibromopropane, and 1,4-dibromobutane.
In this step, copper (I) bromide or the like can be used as a catalyst.
This step is generally based on the compound represented by formula (II) 1 mole, using a base of 0.5 mole to 5 moles, preferably 1 to 2 moles, and an alkylating agent of 0.5 moles to 5 moles, It is preferably performed at 1 to 3 moles.
The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, isopropyl alcohol, tertiary butanol, toluene, benzene, dichloromethane, chloroform, tetrahydrofuran, dioxane, and N, N-dioxane are preferred. Methylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfinium, etc., or a mixed solvent thereof.
The reaction temperature is usually -78 ° C to the reflux temperature of the solvent, preferably 0 ° C to room temperature.
The reaction time is usually 10 minutes to 24 hours, preferably 10 minutes to 1 hour.
(Step 2) This step is performed by using the compound represented by formula (III) and the compound represented by formula (IV)._N A step of reacting Ar to produce a compound represented by formula (V).
PG₁ And PG₂ There is no particular limitation as long as it is a conventional amine protecting group, as PG₁ , Preferably 2,4,6-trimethoxybenzyl, 2,4-dimethoxybenzyl or 4-methoxybenzyl, as PG₂ Is preferably a third butoxycarbonyl group, a benzyloxycarbonyl group or a 4-methoxybenzyl group.
This step is usually carried out using 0.5 to 5 mols, preferably 1 to 2 mols of the compound represented by formula (IV) with respect to 1 mol of the compound represented by formula (III).
Examples of the base used in this step include triethylamine, diisopropylethylamine, pyridine, dimethylpyridine, trimethylpyridine, 4-dimethylaminopyridine, and third butyric acid. Potassium, sodium tertiary butyrate, sodium methoxide, sodium ethoxide, lithium bis (trimethylsilane) amine, sodium bis (trimethylsilane) amine, potassium bis (trimethylsilane) amine, butyllithium And other organic bases, or inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, sodium phosphate, and potassium phosphate.
The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, isopropyl alcohol, tertiary butanol, toluene, benzene, dichloromethane, chloroform, tetrahydrofuran, dioxane, and N, N-dimethyl are preferred. Methylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfinium, etc., or a mixed solvent thereof.
The reaction temperature is usually 0 ° C to 200 ° C, preferably 80 ° C to 180 ° C.
The reaction time is usually 10 minutes to 3 days, preferably 1 hour to 10 hours.
[Chemical 5]

[Where, R_1a , R₂ , R₇ , R₈ , R₉ , R₁₂ , X₁ , X₂ And X₃ Synonymous with the above. X_3b In the dotted line (When) is a single bond, it is NH or CHR_10a , CR in the case where the dotted line is a double bond_10a . R_{1 0a} B (OR₁₁ )₂ , Or halo. X₄ Represents a hydrogen atom or a halogen group. R₁₁ Synonymous with the above]
(Step 3) This step is a step of producing a compound represented by the formula (X) by a cross coupling reaction between the compound represented by the formula (VIII) and the compound represented by the formula (IX).
This step can be applied, for example, the well-known Suzuki coupling reaction, Negishi reaction, and the aromatic amine synthesis method reported by Buchwald or Hartwig et al. From an aryl halide and an amine in the presence of a palladium catalyst.
This reaction can be performed, for example, by heating in a suitable solvent in the presence or absence of a palladium catalyst in a range of 20 ° C to 200 ° C.
Examples of usable palladium catalysts include palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, and dichloro [1,1'-bis (di Phenylphosphino) ferrocene] palladium, dichlorobisacetonitrile palladium, tris (dibenzylideneacetone) dipalladium (0).
The amount of the palladium catalyst that can be used is preferably in the range of 0.001 to 1 mole relative to 1 mole of the compound represented by formula (VIII).
1-1'-bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9'-dimethyl as needed2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl, 2-di Tributylphosphino-3,4,5,6-tetramethyl-2 ', 4', 6'-triisopropylbiphenyl and the like are used as palladium ligands.
The usable reaction solvent is not particularly limited as long as it does not participate in the reaction. Examples include ethers such as tetrahydrofuran and 1,4-dioxane, alcohols such as methanol and ethanol, and N, N-dimethyl Methylamine, N, N-dimethylacetamidamine, N-methyl-2-pyrrolidone and other amines, benzene, toluene and other hydrocarbons, acetonitrile, dimethylmethylene, water, or the like Mixed solvents.
In this step, as the base, for example, potassium third butyrate, sodium third butyrate, sodium methoxide, sodium ethoxide, lithium bis (trimethylsilyl) amine, sodium bis (trimethylsilyl) amine, Organic bases such as potassium bis (trimethylsilyl) amino, butyllithium, or inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium phosphate, and potassium phosphate.
The reaction time varies depending on the type of the raw materials used and the reaction temperature, and it is usually preferably in the range of 30 minutes to 24 hours.
[Chemical 6]



[Where, R₂ , R₁₂ , X₁ And X₂ Synonymous with the above. R_1b For hydrogen atom, cyano, CO₂ R₁₁ , Or with R₁ Synonymous. R₁₃ For PG₂ , Or formula (XIII)
[Chemical 7]



(Where, R₇ , R₈ And R₉ (Synonymous with above)
The substituents indicated. PG₂ Synonymous with the above]
(Step 4) This step is a step of reducing a compound represented by formula (XI) to produce a compound represented by formula (XII).
In this step, for example, acetonitrile, ethyl acetate, THF, methanol, ethanol, DMF, DMA, NMP, etc. can be used in a suitable solvent that does not hinder the reaction. / Carbon, palladium hydroxide / carbon, etc. are used as catalysts. This step is generally performed with a catalyst of 0.01 to 5 mol, preferably 0.05 to 1 mol, relative to 1 mol of the compound represented by formula (XI). The reaction temperature is usually from room temperature to the reflux temperature of the solvent. The reaction time is usually 1 hour to 24 hours.
[Chemical 8]



[Where, R_1b , R₂ , R₁₂ , R₁₃ , X₁ , X₂ And X₃ Synonymous with the above. R_1C Represents a halogen group]
(Step 5) This step is a step of halogenating a compound represented by the formula (XIV) to produce a compound represented by the formula (XV).
This step can be performed using N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine, and iodine. The solvent is not particularly limited as long as it does not interfere with the reaction. For example, the solvent can be carried out in a suitable solvent that does not interfere with the reaction, such as acetonitrile, ethyl acetate, THF, methanol, ethanol, DMF, DMA, and NMP. The reaction temperature is usually 0 ° C to 100 ° C, preferably room temperature to reflux temperature. The reaction time is usually 10 minutes to 3 days, preferably 30 minutes to 24 hours.
(Step 6) This step is a cyanation reaction of a compound represented by formula (XV) with sodium cyanide, potassium cyanide, or the like, or a cross-coupling reaction with an organic boron reagent, an organic tin reagent, an organic zinc reagent, and the like. Or a step of producing a compound represented by formula (XVI) by an ester synthesis reaction in which carbon monoxide is inserted. This reaction can be performed, for example, by heating in a suitable solvent in the presence or absence of a palladium catalyst in a range of 20 ° C to 200 ° C. Examples of usable palladium catalysts include palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, and dichloro [1,1'-bis (di Phenylphosphino) ferrocene] palladium, dichlorobisacetonitrile palladium, tris (dibenzylideneacetone) dipalladium (0). The amount of the palladium catalyst that can be used is preferably in the range of 0.001 to 1 mole relative to 1 mole of the compound represented by the formula (XV). 1-1'-bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9'-dimethyl as needed2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl, 2-di Tributylphosphino-3,4,5,6-tetramethyl-2 ', 4', 6'-triisopropylbiphenyl and the like are used as palladium ligands.
In this step, as the base, for example, potassium third butyrate, sodium third butyrate, sodium methoxide, sodium ethoxide, lithium bis (trimethylsilyl) amine, sodium bis (trimethylsilyl) amine, Organic bases such as potassium bis (trimethylsilyl) amino, butyllithium, or inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium phosphate, and potassium phosphate.
The usable reaction solvent is not particularly limited as long as it does not participate in the reaction. Examples include ethers such as tetrahydrofuran and 1,4-dioxane, alcohols such as methanol and ethanol, and N, N-dimethyl Methylamine, N, N-dimethylacetamidamine, N-methyl-2-pyrrolidone and other amines, benzene, toluene and other hydrocarbons, acetonitrile, dimethylmethylene, water, or the like Mixed solvents. The reaction time varies depending on the type of the raw materials used and the reaction temperature, and it is usually preferably in the range of 30 minutes to 24 hours.
[Chemical 9]



[Where, R₂ , R₁₂ , R₁₃ , X₁ , X₂ And X₃ Synonymous with the above. R₁₄ Is a hydrogen atom, a substituted alkyl group, or a substituted cycloalkyl group]
(Step 7) This step is a step of producing a compound represented by the formula (XVIII) by reacting a compound represented by the formula (XVII) with a hydroxylamine. The hydroxylamine may be used in the form of an aqueous solution or a salt such as hydrochloric acid and a base may be appropriately used in combination. Examples of the base include organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as sodium carbonate and potassium phosphate. The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, methanol, ethanol, propanol, isopropanol, tertiary butanol, toluene, benzene, dichloromethane, chloroform, tetrahydrofuran, and 1,4 are preferred. -Dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfinium, etc., or a mixed solvent thereof. The reaction temperature is usually from 0 ° C to the reflux temperature of the solvent, preferably from room temperature to the reflux temperature of the solvent. The reaction time is usually 10 minutes to 24 hours, preferably 10 minutes to 1 hour.
(Step 8) This step is a step of producing a compound represented by the formula (XIX) from a compound represented by the formula (XVIII) by deuteration and cyclization reactions. As the halogenating agent, R having₁₄ Carboxylic anhydride, mixed anhydride, chloro, or carboxylic acid. The second cyclization reaction can be carried out by using an excess of the above-mentioned sulfonating agent, or can be carried out by using triphenylphosphine-carbon tetrabromide, phosphonium chloride, propylphosphonic anhydride (cyclic trimer), or Dehydration condensation agents, such as dicyclohexylcarbodiimide, are performed. The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like or a mixed solvent thereof. The reaction temperature is usually from 0 ° C to the reflux temperature of the solvent, preferably from room temperature to the reflux temperature of the solvent. The reaction time is usually 10 minutes to 24 hours, preferably 10 minutes to 1 hour.
(Step 9) This step is a step of producing a compound represented by formula (XX) from a compound represented by formula (XIX) by an isomerization reaction. This step can be performed by, for example, toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N- In a reaction solvent such as methylpyrrolidone or a mixed solvent thereof, hydroxylamine is allowed to react. The reaction solvent is not particularly limited as long as it does not interfere with the reaction. The reaction temperature is usually from 0 ° C to the reflux temperature of the solvent, preferably from room temperature to the reflux temperature of the solvent. The reaction time is usually 10 minutes to 24 hours, preferably 10 minutes to 1 hour.
[Chemical 10]


[Where, R₂ , R₁₁ , R₁₂ , R₁₄ , X₁ And X₂ Synonymous with the above. X₄ Represents an oxygen atom or a sulfur atom. R₁₅ Is a hydrogen atom, a halogen group, or formula (XXIV)
[Chemical 11]



(Where, X₃ And R₁₃ (Synonymous with above)
Represented substituents]
(Step 10) This step is a step of producing a compound represented by formula (XXII) from a compound represented by formula (XXI) and hydrazine. Hydrazine can be used in the form of a hydrate or a salt such as hydrochloric acid. When a carboxylic acid is used as a raw material, as an activator, a dehydration condensation agent such as carbonyldiimidazole, phosphinochloride, propylphosphonic anhydride (cyclic trimer), or dicyclohexylcarbodiimide can be used. The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, ethanol, propanol, toluene, benzene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and N are preferred. N-dimethylacetamidamine, N-methylpyrrolidone, dimethylsulfinium, etc., or a mixed solvent thereof. The reaction temperature is usually from 0 ° C to the reflux temperature of the solvent, preferably from room temperature to the reflux temperature of the solvent. The reaction time is usually 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
(Step 11) This step is a step of producing a compound represented by the formula (XXIII) from a compound represented by the formula (XXII) by deuteration and cyclization reactions. This step can be performed in the same manner as in step 8.
[Chemical 12]


(Where, R_1a , R₂ , R₃ , R₄ , R₅ , R₆ , R₁₅ , X₁ And X₂ Synonymous with the above. R₁₆ Represents a halogen group, or a leaving group such as tosylsulfonyl, methanesulfonyl, or trifluoromethanesulfonyl. R₁₇ (Halo group)
(Step 12) This step is a step of reducing a nitro group of a compound represented by the formula (XXV) to produce a compound represented by the formula (XXVI). This step can be carried out by a hydrogenation reaction using a catalyst such as palladium on carbon, or a reaction using a metal such as iron, zinc, or tin (II) chloride as a reducing agent. The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, methanol, ethanol, propanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and N, N are preferred. -Dimethylacetamide, N-methylpyrrolidone, dimethylsulfinium, etc., or a mixed solvent thereof. The reaction temperature is usually from 0 ° C to the reflux temperature of the solvent, preferably from room temperature to the reflux temperature of the solvent. The reaction time is usually 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
(Step 13) This step is a step of producing a compound represented by the formula (XXVII) by a reductive amination reaction of a compound represented by the formula (XXVI) with an aldehyde or an equivalent thereof. As the aldehyde or its equivalent used in this step, 1,4-dioxane-2,5-diol, 2-hydroxyacetaldehyde, and the like can be used. As the reducing agent, sodium borohydride, sodium cyanoborohydride, sodium triethoxyalkoxyborohydride, or the like can be used. The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, methanol, ethanol, propanol, toluene, benzene, tetrahydrofuran, 1,4-dioxane, and N, N-dimethylformamide are preferred. , N, N-dimethylacetamidamine, N-methylpyrrolidone, dimethylsulfinium, etc., or a mixed solvent thereof. The reaction temperature is usually from 0 ° C to the reflux temperature of the solvent, preferably from room temperature to the reflux temperature of the solvent. The reaction time is usually 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
(Step 14) This step is a step of converting a hydroxyl group of a compound represented by the formula (XXVII) into a leaving group such as a halo group and a mesylsulfonyl group to produce a compound represented by the formula (XXVIII). As conditions for the sulfonyl esterification, conditions using a suitable base such as methanesulfonyl chloride, tosylsulfonyl chloride and the like can be exemplified. Examples of the conditions used for the halogenation include the conditions of using a halogenating agent such as carbon tetrachloride, carbon tetrabromide, or iodine, and triphenylphosphine, or the treatment of the above-mentioned sulfonyl esters with lithium halides to convert them to halogens. Conditions.
The compound represented by the formula (XXVIII) can also be synthesized from the compound represented by the formula (XXVI) by direct reductive amination and the like. In this case, 2-chloroacetaldehyde, 2-bromoacetaldehyde, or the like can be used as the aldehyde, and synthesized in the same manner as in Step 13.
(Step 15) In this step, the compound represented by formula (XXVIII) and HNR are used.₃ R₄ A step of producing a compound represented by formula (XXIX) by reacting the represented amine. This step can be done by using excess HNR₃ R₄ As indicated by the amine, or by HNR due to the presence of a suitable base₃ R₄ The indicated amine action proceeds. This step can be performed without using a solvent. In the case of using a solvent, for example, ethanol, propanol, toluene, benzene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfinium, etc., or a mixed solvent thereof. The reaction temperature is usually from 0 ° C to the reflux temperature of the solvent, preferably from room temperature to the reflux temperature of the solvent. The reaction time is usually 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
(Step 16) This step is to use the compound represented by formula (XXX) and formula (XXXI)
[Chemical 13]



(Where, R₃ , R₄ , R₅ And R₆ (Synonymous with above)
A step of producing a compound represented by formula (XXIX) by reacting the represented amine. This step can be performed by using an excess of the amine represented by the formula (XXXI) or by using an amine represented by the formula (XXXI) and a suitable base. In this reaction, a catalyst such as palladium or copper can be used. Examples of usable palladium catalysts include palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, and dichloro [1,1'-bis (di Phenylphosphino) ferrocene] palladium, dichlorobisacetonitrile palladium, tris (dibenzylideneacetone) dipalladium (0), and the like.
The amount of the palladium catalyst that can be used is preferably in the range of 0.001 to 1 mole relative to 1 mole of the compound represented by formula (XXX).
1-1'-bis (diphenylphosphino) ferrocene, 4,5-bis (diphenylphosphino) -9,9'-dimethyl as needed2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl, 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl, 2-di Tributylphosphino-3,4,5,6-tetramethyl-2 ', 4', 6'-triisopropylbiphenyl and the like are used as palladium ligands.
In this step, as the base, for example, triethylamine, diisopropylethylamine, potassium third butyrate, sodium third butyrate, sodium methoxide, sodium ethoxide, and bis (trimethylsilyl) amine group can be used. Organic bases such as lithium, sodium bis (trimethylsilane) amine, potassium bis (trimethylsilane) amino, or inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium phosphate, and potassium phosphate. As the reaction solvent, ethanol, propanol, toluene, benzene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-formaldehyde Pyrrolidone, dimethylsulfinium, etc., or a mixed solvent thereof. The reaction temperature is usually from 0 ° C to the reflux temperature of the solvent, preferably from room temperature to the reflux temperature of the solvent. The reaction time is usually 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
(Step 17) This step is to use the compound represented by formula (XXX) and formula (XXXII)
[Chemical 14]



(Where, R₅ And R₆ Synonymous with the above. R₁₈ A step of producing a compound represented by formula (XXVII) by reacting an amine represented by a protecting group or a hydrogen atom). This step can be performed in the same manner as (step 16).
The compound of the present invention or a salt thereof may be amorphous or crystalline. The compound of the present invention or a salt thereof includes both a single crystal and a polycrystalline mixture. Crystals can be produced by crystallization by applying a known crystallization method. The compound of the present invention or a salt thereof may be a solvate (for example, a hydrate, etc.) or may be an unsolvated compound. The compound of the present invention or a salt thereof includes both of them. The compounds of the invention or their salts also include isotopic elements (e.g.³ H,¹⁴ C,³⁵ S,¹²⁵ I, etc.) and other labeled compounds.
The salt of the compound of the present invention means a pharmaceutically acceptable salt.
The compounds of the present invention or their salts also include their prodrugs. A prodrug is a compound that is converted into a compound of the present invention or a salt thereof by a reaction caused by an enzyme or gastric acid under physiological conditions in the living body, that is, the compound of the present invention is converted into a compound of the present invention or undergoes enzymatic oxidation, reduction, hydrolysis, or the like. The compound of the salt thereof is hydrolyzed by the action of gastric acid and the like to become the compound of the present invention or the salt thereof. In addition, it can also be a compound of the present invention or a salt thereof under physiological conditions as described in Guangchuan Bookstore 1990 "Development of Pharmaceuticals" Volume 7, Molecular Design, pages 163 to 198.
In one embodiment, the compound of the present invention or a salt thereof has excellent Akt inhibitory activity. "Akt" mentioned in this specification includes human or non-human mammals, preferably human Akt. "Akt" includes plural isoforms. For example, when Akt is a human Akt, it includes Akt1, Akt2, and Akt3. In one embodiment, the compound of the present invention or a salt thereof has inhibitory activity on at least one of these subtypes, preferably two or more types, more preferably three or more types, and even more preferably all subtypes. Specifically, Akt1 or Akt2 is preferable, and Akt1 is more preferable. The inhibitory activity of the compounds of the present invention on Akt can be determined by conventional methods known in the art (Biochem. J. vol. 385, pp399-408 (2005) and Cancer Res. Vol. 68, pp2366-2374 (2008)).
In one embodiment, the compound of the present invention or a salt thereof has excellent Rsk inhibitory activity. "Rsk" mentioned in this specification includes Rsk of human or non-human mammals, preferably human Rsk. "Rsk" includes plural subtypes. For example, when Rsk is a human Rsk, it includes Rsk1 (RPS6KA1), Rsk2 (RPS6KA3), Rsk3 (RPS6KA2), and Rsk4 (RPS6KA6). In one embodiment, the compound of the present invention or a salt thereof has inhibitory activity on at least one of these subtypes, preferably two or more types, more preferably three or more types, and even more preferably all subtypes. Specifically, it is preferably Rsk1. The inhibitory activity of the compounds of the present invention on Rsk can be determined by conventional methods known in the art (Biol. Pharm. Bull. Vol. 39. pp547-555 (2016)).
In one embodiment, the compound of the present invention or a salt thereof has excellent S6K inhibitory activity. "S6K" mentioned in this specification includes S6K of human or non-human mammals, preferably human S6K. Further, "S6K" includes a plurality of subtypes. For example, when S6K is a human S6K, it includes S6K1 (RPS6KB1) and S6K2 (RPS6KB2). In one embodiment, the compound of the present invention or a salt thereof has inhibitory activity on at least one of these subtypes, and preferably all subtypes. Specifically, it is preferably S6K1. The inhibitory activity of the compounds of the present invention on S6K can be determined by conventional methods known in the art (J. Biol. Chem. Vol. 285. pp. 4587-4594 (2010)).
In one embodiment, the compound of the present invention or a salt thereof is useful as a medicine for preventing or treating an Akt-related disease due to its excellent inhibitory activity on Akt. The "Akt-related diseases" include diseases in which Akt has a loss of function, its function is inhibited and / or blocked to reduce the incidence, alleviate symptoms, alleviate, and / or cure the disease.
In one embodiment, the compound of the present invention or a salt thereof is useful as a medicine for preventing or treating Rsk-related diseases due to its excellent inhibitory activity of Rsk. The "disease related to Rsk" includes diseases in which the incidence of Rsk is reduced, the symptoms are alleviated, alleviated, and / or cured by making Rsk lose its function, suppressing and / or blocking its function.
In one embodiment, the compound of the present invention or a salt thereof is useful as a medicine for preventing or treating S6K-related diseases due to its excellent S6K inhibitory activity. The "S6K-related diseases" include diseases in which the incidence of S6K is reduced, the function is suppressed, and / or impeded, thereby reducing the incidence, relieving, alleviating, and / or curing the symptoms.
Examples of "Akt-related diseases", "Rsk-related diseases", or "S6K-related diseases" include, but are not limited to, cancer, autoimmune diseases, and macroglobulinemia. Wait. The tumors to be targeted by the present invention are not particularly limited, and examples thereof include head and neck cancer, digestive system cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (such as gallbladder and bile duct cancer), pancreatic cancer, and colorectal cancer. (Colorectal cancer, colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, genital cancer (ovarian cancer, uterine cancer (cervical cancer, uterine body cancer) Etc.), urinary system cancer (kidney cancer, bladder cancer, prostate cancer, testicular tumor, etc.), hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors, skin cancer, brain tumors Wait. The tumors to be the subject of the present invention are preferably digestive system cancer and reproductive system cancer, and more preferably colorectal cancer and uterine body cancer.
In one embodiment, the compound of the present invention or a salt thereof simultaneously inhibits at least two selected from the group consisting of Akt, Rsk, and S6K. For example, the compound of the present invention or a salt thereof inhibits both Akt and Rsk. For example, the compound of the present invention or a salt thereof inhibits both Akt and S6K. For example, the compound of the present invention or a salt thereof inhibits both Rsk and S6K. For example, the compound of the present invention or a salt thereof inhibits both Akt, Rsk and S6K. By simultaneously inhibiting at least two members selected from the group consisting of Akt, Rsk, and S6K with a single compound, it is expected to reduce side effects and obtain a synergistic therapeutic effect compared to the case where the compounds are simultaneously inhibited with a plurality of compounds.
When the compound of the present invention or a salt thereof is used as a medicine, a pharmaceutical carrier is formulated as necessary, and various administration forms can be adopted according to the purpose of prevention or treatment. Examples of the form include oral preparations, injections, suppositories, ointments, In any form such as an inhaler or a patch, an oral agent is preferably used. Each of these administration forms can be manufactured by a conventional preparation method well-known to a person skilled in the art.
As a pharmaceutically acceptable carrier, various organic or inorganic carrier substances that are conventionally used as preparation materials can be used. For solid preparations, they can be formulated in the form of excipients, binding agents, disintegrating agents, lubricants, and coloring agents. For liquid preparations, It is formulated in the form of solvents, dissolution aids, suspending agents, isotonic agents, buffering agents, soothing agents and the like. Moreover, you may use preparation additives, such as a preservative, an antioxidant, a coloring agent, a sweetener, and a stabilizer, as needed.
When preparing a solid preparation for oral administration, an excipient may be added to the compound of the present invention, and a binding agent, a disintegrating agent, a lubricant, a coloring agent, a flavoring / odorizing agent, etc. may be added as necessary, and then a lozenge may be manufactured by a conventional method. , Coated tablets, granules, powders, capsules, etc.
In the case of preparing an injection, a pH adjusting agent, a buffer, a stabilizer, an isotonicity agent, a local anesthetic, and the like can be added to the compound of the present invention, and a subcutaneous, intramuscular, and intravenous injection can be produced by a conventional method.
The amount of the compound of the present invention to be formulated in each of the above-mentioned administration units is not fixed according to the symptoms of the patient to whom it is applied, or its dosage form, etc. Generally, it is preferable to take the oral administration in the administration unit form. It is about 0.05-1000 mg when injected, 0.01-500 mg when injected, and 1-1000 mg when taken.
In addition, the daily dosage of the medicament having the above-mentioned administration form varies depending on the patient's symptoms, weight, age, gender, etc., and cannot be generalized. As a compound of the present invention, generally, an adult (50 kg) is administered about 0.05 per day. It may be administered in an amount of -5000 mg, preferably 0.1-1000 mg, and preferably administered once a day or divided into about 2-3 times.
[Example]
The following examples and test examples are used to describe the present invention in more detail, but the present invention is not limited by these examples.
As long as the various reagents used in the examples are not specifically described, commercially available products are used. Silica column chromatography and alkaline silica column chromatography use pre-packed columns manufactured by Shoko Scientific or Biotage. The NMR spectrum uses an AL400 (400 MHz; JEOL) or Mercury400 (400 MHz; Varian) type spectrometer. When tetramethylsilane is included in the heavy solvent, tetramethylsilane is used as the internal reference. In other cases, the measurement is performed using an NMR solvent as an internal reference, and the total δ value is expressed in ppm. The microwave reaction was performed using an Initiator (registered trademark) manufactured by Biotage.
The LCMS (Liquid Chromatography-Mass Spectrometry) was measured using SQD manufactured by Waters under the following conditions.
Column: Acquity BEH C18, 2.1 × 50 mm, 1.7 μm
MS detection: ESI positive
UV detection: 254 and 210 nm
Column flow rate: 0.5 mL / min
Mobile phase: water / acetonitrile (0.1% formic acid)
Injection volume: 1 μL
gradient
Time (min) Water Acetonitrile
0 95 5
0.1 95 5
2.1 5 95
3.0 stop
The meaning of the abbreviation is as follows.
s: singlet
d: doublet
t: triplet
q: quadruple peak
dd: double doublet
dt: double triplet
ddd: both double peaks
m: multiplet
br: wide peak
DMSO-D₆ : Deuterated dimethylsulfine
CDCl₃ : Deuterochloroform
THF: tetrahydrofuran
DMF: N, N-dimethylformamide
DMSO: Dimethyl sulfene
DIPEA: N, N-diisopropylethylamine
HATU: O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate
NBS: N-bromosuccinimide
TFA: trifluoroacetic acid
Reference Example 1 4-Chloro-7- (2,4-dimethoxybenzyl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one ( Reference example (1))
In 4-chloro-7- (2,4-dimethoxybenzyl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (6 g), THF (93.8 ml), To a mixture of potassium tert-butoxide (6.32 g), methyl iodide (3.51 ml) was slowly added dropwise, followed by stirring at room temperature for 2 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain Reference Example (1) of the above title as a white solid.
Reference Example 2 4-chloro-7- (2,4-dimethoxybenzyl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (Reference Example ( 2))
Step 1: Pass Pierik, Antonio J .; Ciceri, Daniele; Broeker, Gerd; Edwards, Christopher H .; McFarlane, William; Winter, Joachim; Buckel, Wolfgang; Golding, Bernard T .; Journal of the American Chemical Society , 124 (47), 14039-14048; 2002. Triethyl propane-1,1,2-tricarboxylate (3.0 g), methanol (7.0 ml), sodium methoxide (25%, A mixture of methanol solution, 0.050 ml) was stirred at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, sodium methoxide (25%, methanol solution, 5.3 g), methanol (2 ml), and formazan acetate (1.3 g) were added, and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added hydrogen chloride (5-10%, methanol solution, 19 ml), and the mixture was stirred at 0 ° C for 15 minutes. The produced solid was collected by filtration, washed with methanol, and dried under reduced pressure to obtain methyl 2- (4,6-dihydroxypyrimidin-5-yl) propanoate (Reference Example (2-1)) ).
Step 2: A mixture of Reference Example (2-1) (1.2 g), phosphonium chloride (3.5 ml), and N, N-diethylaniline (4.0 ml) was stirred at 130 ° C for 3 hours. The obtained mixture was cooled to room temperature, diluted with toluene (40 ml), and poured into ice water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography to obtain methyl 2- (4,6-dichloropyrimidin-5-yl) propanoate as a brown solid (Reference Example (2-2)).
Step 3: Stir the mixture of Reference Example (2-2) (0.50 g), 2,4-dimethoxybenzylamine (0.35 ml), DIPEA (0.44 ml), DMF (5 ml) at 60 ° C 2.5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water, 1N hydrochloric acid, water, and saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was dissolved in toluene (10 ml), and p-toluenesulfonic acid hydrate (20 mg) was added, followed by heating under reflux for 2.5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and a saturated sodium bicarbonate solution in this order. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Ethyl acetate was added to the obtained residue, and the mixture was stirred at room temperature. The generated solid was collected by filtration to obtain Reference Example (2) of the above title as a white solid.
Reference Example 3 7- (2,4-dimethoxybenzyl) -5-methyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxa Boranepentyl-2-yl) -5,6-dihydropyridine-1 (2H) -yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (Reference Example ( 3))
Make 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5,6-dihydropyridine-1 (2H) -carboxyl The third butyl acid (1.0 g) was dissolved in dichloromethane (2.0 ml) and TFA (2.0 ml), and stirred at room temperature for 15 minutes. Reference Example (2) (1.1 g), DMSO (7.0 ml), and DIPEA (2.3 ml) were added to the residue obtained by concentrating and drying the reaction mixture, and stirred at 120 ° C for 4 hours under microwave irradiation. . After cooling to room temperature, water was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography to obtain a reference example (3) of the above title as a white amorphous substance.
Reference Example 4 7- (2,4-dimethoxybenzyl) -4- (4-iodopiperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d ] Pyrimidine-6 (7H) -one (Reference Example (4))
Step 1: A mixture of Reference Example (1) (6.22 g), DIPEA (6.23 ml), 4-hydroxypiperidine (1.99 g) and DMSO (24 ml) was stirred at 130 ° C for 3 hours under microwave irradiation. The reaction mixture was diluted with ethyl acetate, and then washed with water. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 7- (2,4-dimethoxybenzyl) -4- (4-hydroxypiperidin-1-yl) -5 as a yellow solid. , 5-Dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (Reference Example (4-1)).
Step 2: Add iodine (6.81 g), triphenylphosphine (7.04 g), imidazole (1.83 g) to the mixture of Reference Example (4-1) (7.14 g) and THF (89.4 ml) at 0 ° C. The temperature was raised to room temperature and stirred for 1 hour. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography, and then recrystallized with methanol (80 ml). The obtained solid was filtered and dried to obtain Reference Example (4) of the above title as a white powder.
Reference example 5 5,5-dimethyl-4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5 , 6-dihydropyridine-1 (2H) -yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (Reference Example (5))
4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2,3,6-tetrahydropyridine-1- A mixture of a third butyl carboxylic acid (2.25 g), hydrogen chloride (1,4-dioxane solution, 4M, 6 ml), and chloroform (3 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated, and 4-chloro-5,5-dimethyl- synthesized by the method described in Shepherd, Timothy Alan; Dally, Robert Dean; Joseph, Sajan; US20100120801A1. Was added to the obtained residue. 5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (1.31 g), DIPEA (4.62 ml) and DMSO (10 ml), and the mixture was stirred at 140 ° C. overnight. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain a reference example (5) of the above title as a pale yellow amorphous substance.
Example 1 4- (4- (5-((2- (Third-butylamino) ethyl) amino) -5'-fluoro- [2,3'-bipyridyl] -6-yl) piper (Pyridin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (1))
Step 1: 3-amino-2-bromopyridine 4.0 g, 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2,3,6-tetrahydropyridine-1-carboxylic acid third butyl ester (9.0 g), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) chloride -A mixture of dichloromethane complex (1.9 g), 1,4-dioxane (25 ml) and aqueous sodium carbonate (2M, 15 ml) is stirred at 100 ° C for 3 hours. After cooling to room temperature, it was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography to obtain 3-amino-5 ', 6'-dihydro- [2,4'-bipyridine] -1' as a brown oily substance. (2′H) -carboxylic acid third butyl ester (compound (1-1)).
Step 2: A mixture of compound (1-1) (9.0 g), ethyl acetate (80 ml), and 10% palladium on carbon (2.5 g) was stirred at room temperature under a hydrogen atmosphere for 14 hours. After being replaced with nitrogen, the reaction mixture was filtered. The filtrate was concentrated to obtain 4- (3-aminopyridin-2-yl) piperidine-1-carboxylic acid third butyl ester (compound (1-2)) as a brown amorphous substance.
Step 3: In a mixture of compound (1-2) (7.5 g), THF (60 ml) and glycol aldehyde dimer (4.2 g), add 0.5M sodium cyanoborohydride-0.25M chlorine while stirring. A solution of zinc chloride in methanol (30 ml). After the reaction mixture was stirred at room temperature for 16 hours, water and a 28% aqueous ammonia solution were added, and after stirring, the organic solvent was distilled off under reduced pressure. The obtained mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by basic silica gel column chromatography to obtain 4- (3-((2-hydroxyethyl) amino) pyridin-2-yl) piperidine-1- as a pale yellow solid. Third butyl carboxylic acid (compound (1-3)).
Step 4: Add NBS (3.2 g) to a mixture of compound (1-3) (5.5 g) and THF (100 ml), and stir at room temperature for 90 minutes. After adding a saturated sodium bicarbonate solution and a saturated sodium sulfite aqueous solution to the obtained mixture, extraction was performed with chloroform. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by basic silica gel column chromatography to obtain 4- (6-bromo-3-((2-hydroxyethyl) amino) pyridin-2-yl) piperidine as a brown solid. Third butyl carboxylic acid (compound (1-4)).
Step 5: Compound (1-4) (6.9 g) was dissolved in TFA (20 ml) and stirred at room temperature for 30 minutes. After the reaction mixture was concentrated, an ammonia methanol solution (7M, 10 ml) was added to the residue, and the mixture was stirred at room temperature. To the reaction mixture was added brine, and extraction was performed with a chloroform-ethanol mixed solvent (4: 1). The organic layer was separated, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated to obtain 2-((6-bromo-2- (piperidin-4-yl) pyridin-3-yl) amino) ethanol (compound (1-5)) as a brown amorphous substance.
Step 6: A mixture of Compound (1-5) (5.1 g), Reference Example (1) (6.6 g), DMSO (34 ml), and DIPEA (30 ml) was stirred at 150 ° C for 16 hours. After cooling, water was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (4- (6-bromo-3-((2-hydroxyethyl) amino) pyridin-2-yl) piperazine as a brown solid. Pyridin-1-yl) -7- (2,4-dimethoxybenzyl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one ( Compound (1-6)).
Step 7: To a mixture of compound (1-6) (11 g), triphenylphosphine (6.1 g), and THF (90 ml) was added carbon tetrabromide (7.8 g) under cooling in an ice bath. After the obtained mixture was stirred at room temperature for 30 minutes, a saturated sodium bicarbonate solution was added, and extraction was performed with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After the insoluble matter was separated by filtration, the filtrate was concentrated. The obtained residue was recrystallized using a mixed solvent of chloroform (8 ml) and methanol (110 ml). The obtained solid was filtered and dried to obtain 4- (4- (6-bromo-3-((2-bromoethyl) amino) pyridin-2-yl) piperidine-1- as a white solid. ) -7- (2,4-dimethoxybenzyl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (1- 7)).
Step 8: A mixture of compound (1-7) (0.85 g), THF (3 ml), and tert-butylamine (0.66 ml) was stirred at 75 ° C overnight. The reaction mixture was concentrated, and the obtained residue was purified by basic silica gel column chromatography to obtain 4- (4- (6-bromo-3-((2- (third-butyl) Amino) ethyl) amino) pyridin-2-yl) piperidin-1-yl) -7- (2,4-dimethoxybenzyl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (1-8)).
Step 9: Compound (1-8) (0.15 g), 3-fluoropyridine-5-boronic acid (0.050 g), 1,4-dioxane (3.5 ml), aqueous sodium carbonate solution (2M, 0.40 ml), Chlorine (2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1,1'-biphenyl) [2- (2'-amino-1,1'-biphenyl Group)] A mixture of palladium (II) (0.020 g) was stirred at 100 ° C for 2 hours, then allowed to cool and diluted with ethyl acetate. The mixture was washed sequentially with water and saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. After filtering insoluble matter, the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography to obtain 4- (4- (5-((2- (third-butylamino) ethyl) amino) -5) as a white solid. '-Fluoro- [2,3'-bipyridyl] -6-yl) piperidin-1-yl) -7- (2,4-dimethoxybenzyl) -5,5-dimethyl-5H -Pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (1-9)).
Step 10: A mixture of compound (1-9) (0.050 g), anisole (0.2 ml), and TFA (2 ml) was stirred at 140 ° C. for 1 hour under microwave irradiation. The reaction mixture was concentrated, and the obtained residue was purified by basic silica gel column chromatography to obtain the above-identified compound (1).
Example 2 4- (4- (6'-fluoro-5-((2- (pyrrolidin-1-yl) ethyl) amino)-[2,3'-bipyridyl] -6-yl) piper (Pyridin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (2))
According to Example 1, pyrrolidine was used in place of the third butylamine, and 2-fluoropyridine-5-boronic acid was used in place of 3-fluoropyridine-5-boronic acid to obtain the above-identified compound (2).
Example 3 4- (4- (6- (1,3-dimethyl-1H-pyrazol-5-yl) -3-((2- (pyrrolidin-1-yl) ethyl) amino) Pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (3))
According to Example 1, pyrrolidine was used in place of the third butylamine, and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborone was used. Cyclopentyl-2-yl) pyrazole was used in place of 3-fluoropyridine-5-boronic acid to obtain the above-identified compound (3).
Example 4 4- (4- (3-((2- (Third-butylamino) ethyl) amino) -6- (1-difluoromethyl) -1H-pyrazol-4-yl) Pyridine-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (4))
According to Example 1, 1- (difluoromethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine The azole was substituted for 3-fluoropyridine-5-boronic acid to obtain the above-identified compound (4).
Example 5 4- (4- (5 ', 6'-difluoro-5-((2- (isopropylamino) ethyl) amino)-[2,3'-bipyridine] -6- (Yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (5))
According to Example 1, isopropylamine was used instead of the third butylamine, and 2,3-difluoropyridine-5-boronic acid pinacol ester was used instead of 3-fluoropyridine-5-boronic acid to obtain the above-titled compound ( 5).
Example 6 4- (4- (6- (2,4-dimethylthiazol-5-yl) -3-((2- (isopropylamino) ethyl) amino) pyridin-2-yl ) Piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (6))
According to Example 1, isopropylamine was used instead of third butylamine, and 2,4-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxane Boranepentyl-2-yl) -1,3-thiazole in place of 3-fluoropyridine-5-boronic acid to obtain the above-identified compound (6).
Example 7 4- (4- (5'-methoxy-5-((2- (pyrrolidin-1-yl) ethyl) amino)-[2,3'-bipyridine] -6-yl ) Piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (7))
According to Example 1, pyrrolidine was used instead of the third butylamine, and 3-methoxypyridine-5-boronic acid pinacol ester was used instead of 3-fluoropyridine-5-boronic acid to obtain the above-identified compound (7).
Example 8 4- (4- (5'-fluoro-5-((2- (pyrrolidin-1-yl) ethyl) amino)-[2,3'-bipyridyl] -6-yl) piperazine (Pyridin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (8))
According to Example 1, pyrrolidine was used in place of the third butylamine to obtain the above-identified compound (8).
Example 9 4- (4- (6- (3-chloro-1-methyl-1H-pyrazol-5-yl) -3-((2- (dimethylamino) ethyl) amino) Pyridine-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (9))
According to Example 1, dimethylamine (2M, THF solution) was used instead of the third butylamine, and 3-chloro-1-methyl-5- (4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl) pyrazole was used in place of 3-fluoropyridine-5-boronic acid to obtain the above-identified compound (9).
Example 10 4- (4- (3-((2- (isopropylamino) ethyl) amino) -6- (1-methyl-3- (trifluoromethyl) -1H-pyrazole -5-yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (10 ))
According to Example 1, isopropylamine was used instead of third butylamine, and 1-methyl-3-trifluoromethylpyrazole-5-boronic acid was used instead of 3-fluoropyridine-5-boronic acid to obtain the title of Compound (10).
Example 11 4- (4- (6- (3-chloro-1-methyl-1H-pyrazol-5-yl) -3-((2- (isopropylamino) ethyl) amino) Pyridine-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (11))
According to Example 1, isopropylamine was used instead of third butylamine, and 3-chloro-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxo Heteroboranepentyl-2-yl) pyrazole was used in place of 3-fluoropyridine-5-boronic acid to obtain the above-identified compound (11).
Example 12 4- (4- (5-((2- (ethylamino) ethyl) amino) -5'-fluoro- [2,3'-bipyridyl] -6-yl) piperidine- 1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (12))
According to Example 1, ethyl amine (2M, THF solution) was used instead of the third butyl amine to obtain the above-identified compound (12).
Example 13 4- (4- (2'-fluoro-5-((2- (pyrrolidin-1-yl) ethyl) amino)-[2,4'-bipyridyl] -6-yl) piperazine (Pyridin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (13))
According to Example 1, the reference example (2) was used instead of the reference example (1), pyrrolidine was used instead of the third butylamine, and 2-fluoropyridine-4-boronic acid was used instead of 3-fluoropyridine-5-boronic acid to obtain the above The title compound (13).
Example 14 4- (4- (6- (furan-3-yl) -3-((2- (pyrrolidin-1-yl) ethyl) amino) pyridin-2-yl) piperidine-1- ) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (Compound 14)
According to Example 1, reference example (2) was used instead of reference example (1), pyrrolidine was used instead of third butylamine, and 3- (4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl) furan was used in place of 3-fluoropyridine-5-boronic acid to obtain the above-identified compound (14).
Example 15 4- (4- (5-((2- (isopropylamino) ethyl) amino) -5'-methoxy- [2,3'-bipyridine] -6-yl) Piperidin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (15))
According to Example 1, reference example (2) was used instead of reference example (1), isopropylamine was used instead of third butylamine, and 3-methoxypyridine-5-boronic acid pinacol ester was used instead of 3-fluoropyridine. -5-boronic acid to obtain the above-identified compound (15).
Example 16 4- (4- (5'-fluoro-2'-methoxy-5-((2- (pyrrolidin-1-yl) ethyl) amino)-[2,4'-bipyridine ] -6-yl) piperidin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (16))
According to Example 1, reference example (2) was used instead of reference example (1), pyrrolidine was used instead of third butylamine, and 5-fluoro-2-methoxypyridine-4-boronic acid was used instead of 3-fluoropyridine-5. -Boric acid to obtain the above-identified compound (16).
Example 17 4- (4- (2'-fluoro-5-((2- (pyrrolidin-1-yl) ethyl) amino)-[2,3'-bipyridyl] -6-yl) piperazine Pyridin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (17))
According to Example 1, the reference example (2) was used instead of the reference example (1), pyrrolidine was used instead of the third butylamine, and 2-fluoropyridine-3-boronic acid was used instead of 3-fluoropyridine-5-boronic acid to obtain the above. The title compound (17).
Example 18 5-methyl-4- (4- (3-((2- (pyrrolidin-1-yl) ethyl) amino) -6- (thien-3-yl) pyridin-2-yl) Piperidin-1-yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (18))
According to Example 1, using Reference Example (2) instead of Reference Example (1), using pyrrolidine instead of third butylamine, and using 3-thienylboronic acid instead of 3-fluoropyridine-5-boronic acid, the above-titled compound was obtained (18).
Example 19 4- (4- (5'-fluoro-5-((2- (pyrrolidin-1-yl) ethyl) amino)-[2,3'-bipyridyl] -6-yl) piper (Pyridin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (19))
According to Example 1, Reference Example (2) was used in place of Reference Example (1), and pyrrolidine was used in place of the third butylamine to obtain the above-identified compound (19).
Example 20 5-methyl-4- (4- (6- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -3-((2- (pyrrolidine -1-yl) ethyl) amino) pyridin-2-yl) piperidin-1-yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (20))
According to Example 1, reference example (2) was used instead of reference example (1), pyrrolidine was used instead of third butylamine, and 1-methyl-3-trifluoromethylpyrazole-5-boronic acid was used instead of 3-fluoro. Pyridine-5-boronic acid to obtain the above-identified compound (20).
Example 21 4- (4- (5-((2- (dimethylamino) ethyl) amino) -5'-methoxy- [2,3'-bipyridine] -6-yl) Piperidin-1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (Compound (21))
According to Example 1, reference example (2) was used instead of reference example (1), dimethylamine (2M, THF solution) was used instead of third butylamine, and 3-methoxypyridine-5-boronic acid pinacol was used An ester was used instead of 3-fluoropyridine-5-boronic acid to obtain the above-identified compound (21).
Example 22 5-methyl-4- (4- (2'-methyl-5-((2- (pyrrolidin-1-yl) ethyl) amino)-[2,3'-bipyridine] -6-yl) piperidin-1-yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (22))
According to Example 1, the reference example (2) was used instead of the reference example (1), pyrrolidine was used instead of the third butylamine, and 2-methylpyridine-3-boronic acid was used instead of 3-fluoropyridine-5-boronic acid. Compound (22) of the above title.
Example 23 4- (4- (3-((2- (dimethylamino) ethyl) amino) -6- (thien-3-yl) pyridin-2-yl) piperidin-1-yl ) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (23))
According to Example 1, reference example (2) was used instead of reference example (1), dimethylamine (2M, THF solution) was used instead of third butylamine, and 3-thienylboronic acid was used instead of 3-fluoropyridine-5- Boric acid to obtain the above-identified compound (23).
Example 24 5-methyl-4- (4- (3-((2- (pyrrolidin-1-yl) ethyl) amino) -6- (thiazol-2-yl) pyridin-2-yl) Piperidin-1-yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (24))
Step 1: According to steps 1 to 8 of Example 1, use Reference Example (2) instead of Reference Example (1), and use pyrrolidine instead of third butylamine to obtain 4- (4- (6-Bromo-3-((2- (pyrrolidin-1-yl) ethyl) amino) pyridin-2-yl) piperidin-1-yl) -7- (2,4-dimethoxy Benzyl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (24-1)).
Step 2: Compound (24-1) (0.044 g), 2- (tributyltinalkyl) thiazole (0.032 ml), bis (triphenylphosphine) palladium (II) chloride (4.7 mg), 1,4 -A mixture of dioxane (1.5 ml) was stirred at 100 ° C for 1 hour under microwave irradiation. The obtained mixture was concentrated, and the residue was purified by basic silica gel column chromatography to obtain 7- (2,4-dimethoxybenzyl) -5-methyl-4 as a pale yellow solid. -(4- (3-((2- (pyrrolidin-1-yl) ethyl) amino) -6- (thiazol-2-yl) pyridin-2-yl) piperidin-1-yl) -5H -Pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (24-2)).
Step 3: According to Step 10 of Example 1, using compound (24-2) in place of compound (1-9), and obtaining the above-identified compound (24).
Example 25 5-methyl-4- (4- (6- (oxazol-2-yl) -3-((2- (pyrrolidin-1-yl) ethyl) amino) pyridin-2-yl ) Piperidin-1-yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (25))
According to Example 24, 2- (trimethylstannyl) oxazole was used instead of 2- (tributyltinalkyl) thiazole to obtain the above-identified compound (25).
Example 26 4- (5-fluoro-5 '-((2- (pyrrolidin-1-yl) ethyl) amino) -5' ', 6' '-dihydro- [3,2': 6 ', 4' '-terpyridine] -1' '(2''H) -yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound ( 26))
Step 1: 5-Bromo-2-chloropyridine (10 g), ethanolamine (6.3 ml), copper (I) iodide (0.99 g), L-proline (1.2 g), potassium carbonate (14 g) The mixture of DMSO (40 ml) was stirred at 100 ° C for 1 hour under microwave irradiation. The obtained mixture was diluted with ethyl acetate, and then filtered, and the filtrate was washed with water and saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2-((6-chloropyridin-3-yl) amino) ethanol (compound (26-1)).
Step 2: The compound (26-1) (7.2 g) was dissolved in THF (150 ml), and after cooling to 0 ° C, NBS (7.4 g) was slowly added. After the reaction mixture was stirred at room temperature for 30 minutes, it was cooled to 0 ° C again, and triphenylphosphine (16 g) and carbon tetrabromide (21 g) were sequentially added. After the reaction mixture was stirred at room temperature for 30 minutes, a 10% sodium sulfite aqueous solution was added, and extraction was performed with ethyl acetate. After the organic layer was separated, it was washed with water and saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. Methanol was added to the obtained residue, and the produced solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain 2-bromo-N- (2-bromoethyl) -6-chloropyridin-3-amine (compound (26-2)) as a white solid.
Step 3: A mixture of compound (26-2) (0.51 g), THF (2 ml), and pyrrolidine (0.30 ml) was stirred at 80 ° C for 30 minutes. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to obtain 2-bromo-6-chloro-N- (2- (pyrrolidin-1-yl) ethyl) pyridin-3-amine (compound (26-3)) as a brown oily substance.
Step 4: Compound (26-3) (0.10 g), Reference Example (3) (0.10 g), dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) A mixture of methyl chloride complex (30 mg), aqueous sodium carbonate solution (2M, 0.30 ml), and 1,4-dioxane (2 ml) was stirred at 115 ° C for 30 minutes, and then ethyl acetate was added at room temperature. , Using water for cleaning. The organic layer was dried over anhydrous sodium sulfate and then concentrated. The obtained residue was purified by basic silica gel column chromatography to obtain 4- (6-chloro-3-((2- (pyrrolidin-1-yl) ethyl) amino) as a pale yellow solid. -5'-6'dihydro- [2,4'-bipyridine] -1 '(2'H) -yl) -7- (2,4-dimethoxybenzyl) -5-methyl- 5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (26-4)).
Step 5: According to Steps 9 and 10 of Example 1, using Compound (26-4) in place of Compound (1-8) to obtain the above-identified Compound (26).
Example 27 5-methyl-4- (4- (5- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -2-((2- (pyrrolidine -1-yl) ethyl) amino) pyridin-3-yl) piperidin-1-yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (27))
Step 1: 3-Bromo-2-fluoropyridine (1.8 g), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) -1,2,3,6-tetrahydropyridine-1-carboxylic acid third butyl ester (3.4 g), tetrakis (triphenylphosphine) palladium (0) (0.60 g), aqueous sodium carbonate solution (2M, 6.5 ml) and 1,4-dioxane (25 ml) were stirred at 110 ° C for 20 hours. After cooling to room temperature, it was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 2-fluoro-5 ', 6'-dihydro- [3,4'-bipyridine] -1' (2'H as a pale yellow solid. ) -Third-butyl carboxylic acid (Compound (27-1)).
Step 2: A mixture of compound (27-1) (2.7 g), ethyl acetate (20 ml), and 20% palladium hydroxide / carbon (1 g) was stirred under a hydrogen atmosphere at room temperature overnight. After being replaced with nitrogen, the reaction mixture was filtered. The filtrate was concentrated to obtain 4- (2-fluoropyridin-3-yl) piperidine-1-carboxylic acid third butyl ester (compound (27-2)) as a pale yellow solid.
Step 3: A mixture of compound (27-2) (0.22 g) and 2-pyrrolidin-1-ylethylamine (2 ml) was stirred at 130 ° C for 7 days. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by basic silica gel column chromatography to obtain 4- (2-((2- (pyrrolidin-1-yl) ethyl) amino) pyridine- as a pale yellow oily substance- 3-yl) piperidine-1-carboxylic acid third butyl ester (compound (27-3)).
Step 4: To a mixture of compound (27-3) (0.17 g) and acetic acid (5 ml) was added NBS (96 mg) at room temperature. After being stirred at room temperature for 40 minutes, the reaction mixture was concentrated. The obtained residue was diluted with ethyl acetate, and washed sequentially with a saturated sodium bicarbonate solution, a saturated sodium sulfite aqueous solution, water, and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography to obtain 4- (5-bromo-2-((2- (pyrrolidin-1-yl) ethyl) amine) as a brown oily substance. ) Pyridine-3-yl) piperidine-1-carboxylic acid tert-butyl ester (Compound (27-4)).
Step 5: Compound (27-4) (0.060 g), tetrakis (triphenylphosphine) palladium (0) (0.023 g), 1,4-dioxane 1 ml, 1-methyl-3-trifluoro A mixture of methylpyrazole-5-boronic acid (77 mg) and an aqueous sodium carbonate solution (2M, 0.20 ml) was stirred at 100 ° C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography to obtain 4- (5- (1-methyl-3- (trifluoromethyl) -1H-pyrazole-5) as a colorless oily substance. -Yl) -2-((2- (pyrrolidin-1-yl) ethyl) amino) pyridin-3-yl) piperidine-1-carboxylic acid third butyl ester (compound (27-5)).
Step 6: The mixture of compound (27-5) (74 mg) and TFA (1 ml) was stirred at room temperature for 30 minutes, and then concentrated. The obtained residue was dissolved in DMSO (1 ml), and Reference Example (2) (42 mg) and DIPEA (0.18 ml) were added, followed by stirring at 130 ° C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography to obtain 7- (2,4-dimethoxybenzyl) -5-methyl-4- (4- (5- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl) -2-((2- (pyrrolidin-1-yl) ethyl) amino) pyridine- 3-yl) piperidin-1-yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (27-6)).
Step 7: According to Step 10 of Example 1, using compound (27-6) in place of compound (1-9), and obtaining the above-identified compound (27).
Example 28 4- (4- (3,5'-difluoro-5-((2- (isopropylamino) ethyl) amino)-[2,3'-bipyridine] -6-yl ) Piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (28))
Step 1: p-Bromo-5-fluoro-3-nitropyridine (1.0 g), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alk-2-yl) -1,2,3,6-tetrahydropyridine-1-carboxylic acid third butyl ester (1.7 g), 1,1'-bis (diphenylphosphino) ferrocene-di A mixture of palladium (II) chloride-dichloromethane complex (66 mg), 1,4-dioxane (15 ml), sodium carbonate (0.96 g), and water (6 ml) was heated under reflux for 16 hours. . The reaction mixture was cooled to room temperature, and then filtered, and the filtrate was diluted with ethyl acetate, and then washed with saturated brine. After the organic layer was separated, it was dried over anhydrous sodium sulfate, and the insoluble matter was separated by filtration. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain 5-fluoro-3-nitro-5 ', 6'-dihydro- [2, as a brown amorphous substance. 4'-Bipyridine] -1 '(2'H) carboxylic acid third butyl ester (Compound (28-1)).
Step 2: According to steps 2 to 10 of Example 1, using compound (28-1) instead of compound (1-1) and isopropylamine instead of third butylamine, to obtain the above-identified compound (28).
Example 29 4- (4- (5-((2- (dimethylamino) ethyl) amino) -5'-fluoro- [2,3'-bipyridyl] -6-yl) piperidine- 1-yl) -5-methyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (29))
Step 1: Add 2,6-dichloro-3-nitro to a mixture of 1- (third butoxycarbonyl) -piper (4.5 g), 2-propanol (30 ml), and DIPEA (6.1 ml) A solution of pyridine (3.8 g) in THF (30 ml) was stirred at room temperature for 2.5 hours. After adding a 10% phosphoric acid aqueous solution to the reaction mixture, the organic solvent was distilled off under reduced pressure. The generated solid was collected by filtration and washed with water. The obtained solid was suspended in ethyl acetate, and the insoluble matter was separated by filtration. The obtained filtrate was washed with a saturated sodium bicarbonate solution and a saturated saline solution in this order, the organic layer was separated, and then dried over anhydrous sodium sulfate. After the insoluble matter was separated by filtration, the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (6-chloro-3-nitropyridin-2-yl) piper-1-carboxylic acid tert-butyl ester (Compound (29-1) ).
Step 2: A mixture of compound (29-1) (1.0 g), ethanol (10 ml), water (2 ml), iron (0.80 g), and ammonium chloride (1.2 g) was stirred at 60 ° C for 1.5 hours. After the reaction mixture was cooled to room temperature, a saturated sodium bicarbonate solution and ethyl acetate were added. After the insoluble matter was separated by filtration, the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (3-amino-6-chloropyridin-2-yl) piper-1-carboxylic acid tert-butyl ester (Compound (29-2) ).
Step 3: Mix a mixture of compound (29-2) (0.94 g), N, N-dimethylglycine (0.45 g), DMF (10 ml), HATU (1.8 g), DIPEA (2 ml) Stir at room temperature for 18 hours. HATU (0.90 g) was added again, and after stirring for 18 hours, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 4- (6-chloro-3- (2- (dimethylamino) acetamido) pyridin-2-yl) piper-1-carboxyl. Acid third butyl ester (compound (29-3)).
Step 4: Boron-methyl sulfide complex (2 ml) was added to a THF solution (10 ml) of compound (29-3) (0.66 g), and the mixture was stirred at room temperature for 18 hours. After slowly adding water, 2N hydrochloric acid (4 ml) was added, and the mixture was stirred at 60 ° C for 12 hours. After the reaction mixture was cooled to room temperature, a 5N sodium hydroxide aqueous solution (5 ml) and di-tert-butyl dicarbonate (1M, THF solution, 1.7 ml) were added, and the mixture was stirred for 24 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography to obtain 4- (6-chloro-3- (2- (dimethylamino) ethyl) amino) pyridin-2-yl) piperate. Tert-butyl-1-carboxylic acid (compound (29-4)).
Step 5: According to steps 5 to 7 of Example 27, use compound (29-4) instead of compound (27-4) and 3-fluoropyridine-5-boronic acid in place of 1-methyl-3-trifluoromethylpyridine Azole-5-boronic acid to obtain the above-identified compound (29).
Example 30 4- (4- (6- (5- (difluoromethyl) -1,3,4-fluorenediazol-2-yl) -3-((2- (pyrrolidin-1-yl) (Ethyl) amino) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound ( 30))
Step 1: Compound (1-6) (2.74 g), 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) chloride-dichloromethane complex (366 mg) The mixture of triethylamine (1.87 ml), N, N-dimethylformamide (8 ml) and methanol (8 ml) was stirred at 0.4 MPa and 80 ° C for 12 hours in a carbon monoxide environment. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 6- (1- (7- (2,4-dimethoxybenzyl) -5,5-dimethyl) as a brown amorphous substance. Methyl-6-oxa-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-yl) -5-((2-hydroxyethyl) amine Methyl) picolinate (compound (30-1)).
Step 2: A mixture of compound (30-1) (2.60 g), hydrazine monohydrate (5 ml) and ethanol (12 ml) was heated under reflux for 1 hour. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 6- (1- (7- (2,4-dimethoxybenzyl) -5,5 as a pale yellow amorphous substance. -Dimethyl-6-oxa-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-yl) -5-((2-hydroxyethyl (Amino) amino) pyridinehydrazine (compound (30-2)).
Step 3: Add difluoroacetic anhydride (0.11 ml) to a mixture of compound (30-2) (500 mg), dichloromethane (8.47 ml), and triethylamine (0.24 ml), and stir at room temperature for 15 minute. Further, difluoroacetic acid (0.11 ml) was added, and after stirring at room temperature for 15 minutes, it was concentrated. An ammonia methanol solution (7M, 8 ml) was added to the residue and the mixture was stirred at room temperature. The mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain N '-(2,2-difluoroethylfluorenyl) -6- (1- ( 7- (2,4-dimethoxybenzyl) -5,5-dimethyl-6-oxa-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-4- Yl) piperidin-4-yl) -5-((2-hydroxyethyl) amino) pyridinecarboxamidine (Compound (30-3)).
Step 4: Mix a mixture of compound (30-3) (621.2 mg), triphenylphosphine (710.5 mg), carbon tetrabromide (898.3 mg), imidazole (207.5 mg), and dichloromethane (8.47 ml) in the chamber. Stir at warm for 3 hours. After further stirring at 40 ° C for 1 hour, triphenylphosphine (710.5 mg) and carbon tetrabromide (898.3 mg) were added, and the mixture was stirred at 40 ° C for 2 days. The mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain the compound (30-4) as a white amorphous substance.
Step 5: According to steps 8 and 10 of Example 1, using compound (30-4) in place of compound (1-7) and pyrrolidine in place of third butylamine, to obtain the above-identified compound (30).
Example 31 4- (4- (6- (5- (difluoromethyl) -1,3,4-fluorenediazol-2-yl) -3-((2- (isopropylamino) ethyl (Amino) amino) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (31 ))
According to Example 30, isopropylamine was used in place of pyrrolidine to obtain the above-identified compound (31).
Example 32 4- (4- (3-((2- (third-butylamino) ethyl) amino) -6- (5- (trifluoromethyl) -1,3,4-fluorene Azole-2-yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound ( 32))
According to Example 30, trifluoroacetic anhydride was used in place of difluoroacetic anhydride, and tributylamine was used in place of pyrrolidine to obtain the above-identified compound (32).
Example 33 4- (4- (3-((2- (isopropylamino) ethyl) amino) -6- (5- (trifluoromethyl) -1,3,4-fluorenediazole -2-yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (33 ))
According to Example 30, trifluoroacetic anhydride was used instead of difluoroacetic anhydride, and isopropylamine was used instead of pyrrolidine to obtain the above-identified compound (33).
Example 34 4- (4- (3-((2- (Third-butyl (methyl) amino) ethyl) amino) -6- (5- (trifluoromethyl) -1,3, 4-fluorenediazol-2-yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H)- Ketone (Compound (34))
According to Example 30, trifluoroacetic anhydride was used instead of difluoroacetic anhydride, and methyltributylamine was used instead of pyrrolidine to obtain the above-identified compound (34).
Example 35 (S) -5,5-dimethyl-4- (4- (3-((pyrrolidin-2-ylmethyl) amino) -6- (5- (trifluoromethyl)- 1,3,4-fluorenediazol-2-yl) pyridin-2-yl) piperidin-1-yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound ( 35))
Step 1: methyl 5-fluoropyridine-2-carboxylate (0.5 g), (S) -2- (aminomethyl) pyrrolidine-1-carboxylic acid third butyl ester (1.0 g), DIPEA ( A mixture of 0.67 ml) and DMSO (3.0 ml) was stirred at 130 ° C for 1.5 hours and at 140 ° C for 1 hour. After cooling to room temperature, it was purified by silica gel column chromatography to obtain (S) -5-(((1- (third-butoxycarbonyl) pyrrolidin-2-yl) as a colorless oily substance. ) Methyl) amino) methyl picolinate (compound (35-1)).
Step 2: To a mixture of compound (35-1) (601 mg) and THF (9 ml) was added NBS (319 mg) at room temperature and stirred for 1 hour. After adding a saturated sodium bicarbonate solution and a saturated sodium sulfite aqueous solution to the obtained mixture, extraction was performed with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography to obtain (S) -6-bromo-5-((((1- (third-butoxycarbonyl) pyrrolidine-2-) Methyl) methyl) amino) picolinate (compound (35-2)).
Step 3: To a mixture of zinc powder (512 mg) and N, N-dimethylacetamide (5 ml), add trimethylchlorosilane (0.06 ml), and stir at room temperature for 10 minutes. Then, reference example (4) (1.2 g) was added, and it stirred at 60 degreeC for 1 hour, and obtained the N, N- dimethylacetamide solution of an organic zinc reagent. In another reaction vessel, add compound (35-2) (649 mg), palladium acetate (35 mg), 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (64 mg), N, N-dimethylacetamide (1.5 ml), and stirred at room temperature for 10 minutes. An N, N-dimethylacetamide solution of the above-mentioned organic zinc reagent was added to the obtained mixture, and the mixture was stirred at 60 ° C for 5 hours. After cooling to room temperature, water (5 ml) and ethyl acetate (5 ml) were added to the reaction mixture, followed by filtration. After the organic layer was separated, it was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained residue was purified by basic silica gel column chromatography to obtain (S) -5-(((1- (third-butoxycarbonyl) pyrrolidine-2- (Yl) methyl) amino) -6- (1- (7- (2,4-dimethoxybenzyl) -5,5-dimethyl-6-oxa-6,7-dihydro- 5H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-yl) methyl picolinate (Compound (35-3)).
Step 4: According to steps 2 to 4 of Example 30, use compound (35-3) instead of compound (30-1), and use trifluoroacetic anhydride instead of difluoroacetic anhydride to obtain (a) S) -Third-butyl 2-(((2- (1- (7- (2,4-dimethoxybenzyl) -5,5-dimethyl-6-oxa-6,7- Dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-yl) -6- (5- (trifluoromethyl) -1,3,4-fluorenediazole- 2-yl) pyridin-3-yl) amino) methyl) pyrrolidine-1-carboxylic acid (compound (35-4)).
Step 5: According to Step 10 of Example 1, using compound (35-4) in place of compound (1-9), and obtaining the above-identified compound (35).
Example 36 5,5-Dimethyl-4- (4- (6- (5-methyl-1,3,4-thiadiazol-2-yl) -3-((2- (pyrrolidine- 1-yl) ethyl) amino) pyridin-2-yl) piperidin-1-yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (36))
Step 1: Add concentrated sulfuric acid (1 ml) to a mixture of 5-bromopicolinic acid (10 g) and methanol (50 ml). After heating and refluxing for 3 hours, the reaction mixture is concentrated. The obtained residue was diluted with ethyl acetate and washed with water, a saturated sodium bicarbonate solution, and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated. Ethanol (50 ml) and hydrazine monohydrate (10 ml) were added to the obtained residue, and the mixture was heated under reflux for 3 hours, and then the reaction mixture was concentrated. Water was added to the obtained residue, and the produced solid was collected by filtration to obtain 5-bromopyridinecarbazide (compound (36-1)) as a yellow solid.
Step 2: Add acetic anhydride (0.79 ml) to a mixture of compound (36-1) (1.5 g), acetonitrile (25 ml), and triethylamine (1 ml), and stir at room temperature for 30 minutes. Water was added to the reaction mixture, and the resulting solid was collected by filtration to obtain N'-acetamido-5-bromopyridinecarbazide (compound (36-2)) as a white solid.
Step 3: After heating a mixture of compound (36-2) (1.78 g), Lawesson's reagent (2.8 g), and 1,4-dioxane (35 ml) for 1 hour, reflux the reaction mixture Concentrate. The residue obtained was purified by silica gel column chromatography. The obtained solid was suspended in methanol: water (5: 1). The solid was collected by filtration to obtain 2- (5-bromopyridin-2-yl) -5-methyl-1,3,4-thiadiazole (compound (36-3)) as a white solid.
Step 4: Compound (36-3) (1.15 g), ethanolamine (0.81 ml), copper (I) iodide (85 mg), L-proline (103 mg), potassium carbonate (1.24 g), and A mixture of DMSO (10 ml) was stirred at 80 ° C overnight. After cooling to room temperature, it was diluted with water and ethyl acetate, filtered, and then extracted three times with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The obtained residue was diluted with methanol, and then a methanolic hydrochloric acid solution was added and concentrated. The obtained residue was suspended in ethyl acetate and filtered. The obtained solid was suspended in chloroform, and a saturated sodium bicarbonate solution was added. After the organic layer was separated, the aqueous layer was extracted five times with chloroform / methanol (10: 1). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was suspended in chloroform. The solid was filtered to obtain 2-((6- (5-methyl-1,3,4-thiadiazol-2-yl) pyridin-3-yl) amino) ethanol (Compound (36 -4)).
Step 5: Add NBS (421 mg) to a mixture of compound (36-4) (559 mg), THF (10 ml), and acetonitrile (5 ml), and stir at room temperature for 30 minutes. An aqueous sodium sulfite solution and a saturated saline solution were added to the reaction mixture, and extraction was performed 5 times with chloroform / methanol (10: 1). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated. Diethyl ether was added to the obtained residue, and the resulting solid was collected by filtration to obtain 2-((2-bromo-6- (5-methyl-1,3,4-thiadiazole-2) as a brown solid. -Yl) pyridin-3-yl) amino) ethanol (compound (36-5)).
Step 6: Add trimethylchlorosilane (0.03 ml) to a mixture of zinc powder (705 mg) and N, N-dimethylacetamide (6 ml), and stir at room temperature for 10 minutes. Then, Reference Example (4) (2.25 g) was added and stirred at 60 ° C. for 30 minutes to obtain a N, N-dimethylacetamide solution of an organic zinc reagent. In another reaction vessel, add compound (36-5) (680 mg), palladium acetate (24 mg), 2-dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl (89 mg), N, N-dimethylacetamide (6 ml), and stirred at room temperature for 10 minutes. An N, N-dimethylacetamide solution of the above-mentioned organic zinc reagent was added to the obtained mixture, and the mixture was stirred at 60 ° C for 5 hours. After cooling to room temperature, (5 ml of water) and ethyl acetate (5 ml) were added to the reaction mixture. After filtration, the organic layer was separated and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained residue was purified by basic silica gel column chromatography to obtain 7- (2,4-dimethoxybenzyl) -4- (4- (3- ( (2-hydroxyethyl) amino) -6- (5-methyl-1,3,4-thiadiazol-2-yl) pyridin-2-yl) piperidin-1-yl) -5,5 -Dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (36-6)).
Step 7: To a mixture of compound (36-6) (804 mg), triphenylphosphine (501 mg), and THF (6 ml) was added carbon tetrabromide (634 mg) under cooling in an ice bath. After the obtained mixture was stirred at room temperature for 1 hour, a saturated sodium bicarbonate solution was added, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by basic silica gel column chromatography to obtain 4- (4- (3-((2-bromoethyl) amino) -6- (5) as a pale yellow amorphous substance. -Methyl-1,3,4-thiadiazol-2-yl) pyridin-2-yl) piperidin-1-yl) -7- (2,4-dimethoxybenzyl) -5,5 -Dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (36-7)).
Step 8: According to steps 8 and 10 of Example 1, using compound (36-7) in place of compound (1-7) and pyrrolidine in place of third butylamine, to obtain the above-identified compound (36).
Example 37 4- (4- (3-((2- (Third-butylamino) ethyl) amino) -6- (5- (difluoromethyl) -1,3,4-thiadi Azole-2-yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound ( 37))
According to Example 36, difluoroacetic anhydride was used instead of acetic anhydride, and tert-butylamine was used instead of pyrrolidine to obtain the above-identified compound (37).
Example 38 4- (4- (6- (5- (difluoromethyl) -1,3,4-thiadiazol-2-yl) -3-((2- (dimethylamino) ethyl Yl) amino) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (38 ))
According to Example 36, difluoroacetic anhydride was used instead of acetic anhydride, and dimethylamine was used instead of pyrrolidine to obtain the above-identified compound (38).
Example 39 4- (4- (6- (5- (difluoromethyl) -1,3,4-thiadiazol-2-yl) -3-((2- (isopropylamino) ethyl (Amino) amino) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (39 ))
According to Example 37, using the isopropylamine instead of the third butylamine, the above-identified compound (39) was obtained.
Example 40 4- (4- (3-((2- (Third-butylamino) ethyl) amino) -6- (5-cyclopropyl-1,3,4-thiadiazole-2 -Yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (40))
According to Example 36, cyclopropanecarboxyphosphonium chloride was used in place of acetic anhydride, and tertiary butylamine was used in place of pyrrolidine to obtain the above-identified compound (40).
Example 41 4- (4- (3-((2- (Third-butylamino) ethyl) amino) -6- (5- (difluoromethyl) -1,2,4-fluorene Azol-3-yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound ( 41))
Step 1: A mixture of 5-fluoro 2-cyanopyridine (25 g), DMSO (100 ml), and 2-aminoethanol (25 ml) was stirred at 75 ° C for 40 minutes. After cooling to room temperature, it was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to obtain 5-((2-hydroxyethyl) amino) -2-cyanopyridine (compound (41-1)) as a white solid.
Step 2: Add NBS (32 g) to a mixture of compound (41-1) (29 g) and THF (300 ml), and stir at room temperature for 3 hours. After adding an aqueous sodium thiosulfate solution (10%, 100 ml) to the obtained mixture, extraction was performed with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was recrystallized from ethyl acetate (110 ml). The obtained solid was collected by filtration, and dried to obtain 6-bromo-5-((2-hydroxyethyl) amino) -2-cyanopyridine (compound (41-2)) as a white solid.
Step 3: Add acetic anhydride (4.0 ml) to a mixture of compound (41-2) (3.4 g) and pyridine (4.0 ml), and stir at room temperature for 30 minutes. The obtained mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtration, it was concentrated, and the obtained residue was recrystallized with isopropyl acetate to obtain 2-((2-bromo-6-cyanopyridine-3-yl) amino) ethyl acetate as a white solid. (Compound (41-3)).
Step 4: Add trimethylchlorosilane (0.089 ml) to a mixture of zinc powder (0.97 g) and N, N-dimethylacetamidamine (5 ml), and make it at 50 ° C under ultrasonic irradiation. React for 15 minutes. After cooling to room temperature, N, N-dimethylacetamide (44 ml) and Reference Example (4) (4.8 g) were added and reacted at 50 ° C for 20 minutes under ultrasonic irradiation. After cooling to room temperature, the excess zinc powder was separated by filtration, and the obtained mixture was added to the separately prepared compound (41-3) (1.8 g), palladium (II) acetate (0.16 g), and dicyclohexyl (2 ', 6'-Dimethoxy- [1,1'-diphenyl] -2-yl) phosphine (0.17 g) and N, N-dimethylacetamide (4 ml), Stir at 70 ° C for 2 hours. After cooling to room temperature, the obtained mixture was diluted with ethyl acetate and water. After filtering insoluble matters, the obtained filtrate was sequentially washed with water and saturated brine, and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain acetic acid 2-((6-cyano-2- (1- (7- ( 2,4-dimethoxybenzyl) -5,5-dimethyl-6-oxa-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-yl) piper Pyridin-4-yl) pyridin-3-yl) amino) ethyl ester (compound (41-4)).
Step 5: Add a hydroxylamine aqueous solution (50%, 2.8 ml) to a mixture of compound (41-4) (8.5 g) and ethanol (100 ml), and stir at 60 ° C for 10 minutes. The obtained mixture was concentrated and dried to obtain acetic acid 2-((2- (1- (7- (2,4-dimethoxybenzyl) -5) as a pale yellow amorphous substance, 5-dimethyl-6-oxa-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-yl) -6- (N-hydroxymethyl Fluorenyl) pyridin-3-yl) amino) ethyl ester (Compound (41-5)).
Step 6: The mixture of compound (41-5) and THF (100 ml) was cooled to 0 ° C, and difluoroacetic anhydride (2.2 ml) and pyridine (25 ml) were sequentially added, and the mixture was stirred at room temperature for 5 minutes. The obtained mixture was further stirred at 60 ° C for 2 hours. After cooling, hydrochloric acid (0.5 M, 30 ml) was added, and extraction was performed with ethyl acetate. After the organic layer was separated, it was sequentially washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering, it was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 2-((6- (5- (difluoromethyl) -1,2,4-fluorenediazol-3-yl) acetic acid as a white solid. ) -2- (1- (7- (2,4-dimethoxybenzyl) -5,5-dimethyl-6-oxa-6,7-dihydro-5H-pyrrolo [2, 3-d] pyrimidin-4-yl) piperidin-4-yl) pyridin-3-yl) amino) ethyl ester (compound (41-6)).
Step 7: Cool the mixture of compound (41-6) (9.8 g), methanol (100 ml) and THF (50 ml) to 0 ° C, add sodium hydroxide aqueous solution (5M, 0.85 ml), and stir at 0 ° C 1 hour. To the obtained mixture was added hydrochloric acid (5M, 0.85 ml), and the mixture was stirred at room temperature for 2 hours. The resulting solid was collected by filtration, washed with methanol (50 ml), and dried under reduced pressure to obtain 4- (4- (6- (5- (difluoromethyl) -1,2,4) as a white solid. -Fluoradiazol-3-yl) -3-((2-hydroxyethyl) amino) pyridin-2-yl) piperidin-1-yl) -7- (2,4-dimethoxybenzyl ) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (41-7)).
Step 8: According to Steps 7, 8 and 10 of Example 1, using compound (41-7) in place of compound (1-6) to obtain the above-identified compound (41).
Example 42 4- (4- (3-((2- (isopropylamino) ethyl) amino) -6- (5- (trifluoromethyl) -1,2,4-fluorenediazole -3-yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound (42 ))
According to Example 41, trifluoroacetic anhydride was used in place of difluoroacetic anhydride and isopropylamine was used in place of third butylamine to obtain the above-identified compound (42).
Example 43 4- (4- (3-((2- (Third-butylamino) ethyl) amino) -6- (3- (trifluoromethyl) -1,2,4-fluorene Azole-5-yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound ( 43))
Step 1: According to steps 1 to 6 of Example 41, trifluoroacetic anhydride was used instead of difluoroacetic anhydride to obtain 2-((2- (1- (7- (2,4-dimethoxybenzyl) ) -5,5-dimethyl-6-oxa-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-yl) -6- ( 5- (trifluoromethyl) -1,2,4-fluorenediazol-3-yl) pyridin-3-yl) amino) ethyl ester (compound (43-1)).
Step 2: A mixture of compound (43-1) (0.44 g), DMF (10 ml), hydroxylamine hydrochloride (0.43 g), and potassium tert-butoxide (0.69 g) was stirred at 70 ° C for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate and then filtered. The obtained filtrate was concentrated to obtain acetic acid 2-((2- (1- (7- (2,4-dimethoxybenzyl) -5,5-dimethyl- 6-oxa-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidin-4-yl) -6- (3- (trifluoromethyl) -1 , 2,4-fluorenediazol-5-yl) pyridin-3-yl) amino) ethyl ester (compound (43-2)).
Step 3: According to Steps 7 and 8 of Example 41, using the compound (43-2) in place of the compound (41-6) to obtain the above-identified compound (43).
Example 44 5,5-Dimethyl-4- (4- (3-((2- (pyrrolidin-1-yl) ethyl) amino) -6- (3- (trifluoromethyl)- 1,2,4-fluorenediazol-5-yl) pyridin-2-yl) piperidin-1-yl) -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (compound ( 44))
According to Example 43, using pyrrolidine in place of the third butylamine, the above-identified compound (44) was obtained.
Comparative Example B 4- (4- (4-((2- (Third-butylamino) ethyl) amino) -5'-fluoro- [2,3'-bipyridyl] -6-yl) piper (Pyridin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one
Step 1: A mixture of 2,6-dibromo-4-nitropyridine (1 g), potassium carbonate (490.3 mg), 2-aminoethanol (0.32 ml) and DMSO (10 ml) was stirred at 60 ° C. 1.5 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 2-((2,6-dibromopyridin-4-yl) amino) ethanol (Comparative Example B (1-1 )).
Step 2: Comparative Example B (1-1) (212 mg), 5-fluoropyridine-3-boronic acid (50 mg), tetrakis (triphenylphosphine) palladium (0) (82.8 mg), sodium carbonate aqueous solution ( A mixture of 2M, 0.39 ml) and 1,4-dioxane (7.16 ml) was stirred at 100 ° C for 1 hour. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 2-((6-bromo-5'-fluoro- [2,3'-bipyridyl] -4-yl) amino group as a crude refined product. ) Ethanol (Comparative Example B (1-2)). The obtained crude refined product was used directly in the next step without further purification.
Step 3: Mix the crude product of Comparative Example B (1-2), carbon tetrabromide (237.6 mg), triphenylphosphine (187.9 mg), THF (3 ml) and dichloromethane (1 ml) in Stir for 30 minutes at room temperature. A saturated sodium bicarbonate solution and water were added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 6-bromo-N- (2-bromoethyl) -5'-fluoro- [2,3'-bipyridine as a yellow amorphous substance. ] -4-amine (Comparative Example B (1-3)).
Step 4: A mixture of Comparative Example B (1-3) (65.7 mg), third butylamine (0.2 ml), and THF (1 ml) was stirred at 80 ° C for 4 hours. A third butylamine (0.2 ml) was added to the reaction mixture, and the mixture was stirred at 90 ° C for 2 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography to obtain N1- (6-bromo-5'-fluoro- [2,3'-bipyridine] -4-yl as a yellow amorphous substance. ) -N2- (third butyl) ethane-1,2-diamine (Comparative Example B (1-4)).
Step 5: Comparative Example B (1-4) (57.5 mg), Reference Example (5) (69.5 mg), 1,1'-bis (diphenylphosphino) ferrocene-palladium dichloride (II )-A mixture of dichloromethane complex (12.8 mg), aqueous sodium carbonate (2M, 0.10 ml) and 1,4-dioxane (1.57 ml) was stirred at 100 ° C for 3 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography to obtain 4- (4 '((2- (third-butylamino) ethyl) amino) -5 as a brown amorphous substance. -Fluoro-5 '', 6 ''-dihydro- [3,2 ': 6', 4 ''-terpyridine] -1 '' (2''H) -yl) -5,5-dimethyl -5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one (Comparative Example B (1-5)).
Step 6: Comparative Example B (1-5) (16 mg), 20% palladium hydroxide / carbon (15 mg), ethyl acetate (1 ml), ethanol (0.1 ml), methanol (0.1 ml), THF (0.1 ml), a mixture of DMF (0.1 ml) and TFA (0.01 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hours. After being replaced with nitrogen, the reaction mixture was filtered. The filtrate was concentrated, and the obtained residue was purified by basic silica gel column chromatography to obtain Comparative Example B of the above title.
The chemical structural formulas and physical properties of the compounds of Examples 1 to 44 are shown in Table 1 below.


[Table 1]











Test Example 1 Confirmation of Akt1 kinase activity inhibitory effect
The preparation of Akt1 and the in vitro inhibitory activity of the compounds of the present invention on Akt1 kinase activity are determined by reference to the literatures of Biochem. J. vol. 385, pp399-408 (2005) and Cancer Res. Vol. 68, pp2366-2374 (2008) Implement the method described. Regarding the preparation of Akt1, firstly, human Akt1 with a Middle T antigen tag was expressed using insect cell Sf9, and then Akt1 was prepared by affinity purification and activation by PDK1, and the inhibitory activity of the compound was determined. Store at -80 ° C before. For the measurement of the inhibitory activity of a compound, Akt1 and this compound were firstly mixed in a reaction buffer (15 mM Tris-HCl pH7.5, 0.01% Tween-20, 2 mM DTT (DL-Dithiothreitol, dithiothreitol)). The inventive compound was pre-incubated at 25 ° C for 120 minutes. Then, biotinylated Crosside (biotin-KGSGSGRPRTSSFAEG, manufactured by Millipore) and MgCl were added so that the final concentrations became 500 nM, 10 mM, and 150 μM, respectively.₂ Reaction with ATP (triphosphate) at 25 ° C for 60 minutes. After the reaction was stopped by adding EDTA (Ethylenediamine Tetraacetic Acid) at a final concentration of 40 mM, Eu-labeled antiphosphorylation was added so that the final concentrations became 0.5 nM and 62.5 nM, respectively. The detection solution of Crosstide antibody (manufactured by PerkinElmer) and SureLight APC-SA (manufactured by PerkinElmer) was reacted at room temperature for 2 hours. Finally, using PHERAstar FS (manufactured by BMG LABTECH) or PHERAstar (manufactured by BMG LABTECH), the amount of fluorescence when irradiated with excitation light at a wavelength of 337 nm was measured at two wavelengths of 620 nm and 665 nm. Determine the amount of phosphorylation reaction based on the ratio of the fluorescence amount of the two wavelengths, and define the concentration of the compound that can inhibit the phosphorylation reaction by 50% as IC₅₀ The value (nM) is shown in Table 2 below.
As comparative compounds, Comparative Example A (WO2010 / 056563 (Example 31)) and Comparative Example B, which are known to have Akt inhibitory activity, were used below.
[Chemical 15]



[Table 2]

Test Example 2 Confirmation of Rsk1 kinase activity inhibitory effect
The in vitro inhibitory activity of the compounds of the present invention on Rsk1 kinase activity was determined using QSS Assist from Carna Biosciences^TM FP detection kit.
As for the measurement of the inhibitory activity of the compound, first, the test compound was diluted stepwise with dimethyl sulfene (DMSO). Next, Rsk1 protein, matrix peptide (final concentration: 100 nM), and a matrix reaction peptide (final concentration: 100 nM) were added to a kinase reaction buffer (20 mM HEPES (pH7.4), 2 mM dithiothreitol (0.01% Tween-20), Magnesium chloride (final concentration 10 mM), ATP (final concentration 30 μM) and the test compound DMSO solution (final DMSO concentration 5%) were incubated at 25 ° C for 40 minutes to perform a kinase reaction. To this, the IMAP Progressive Binding Buffer A of Molecular Devices diluted 400 times was added to the IMAP Progressive Binding Reagent to stop the kinase reaction. After standing at room temperature for 120 minutes in the dark, the amount of phosphorylation reaction can be determined based on the polarization degree of fluorescence measured using PHERAstar (BMG LABTECH, excitation wavelength 485 nm, detection wavelength 520 nm). The concentration of a compound that inhibits the phosphorylation reaction is defined as the IC50 value (nM), and is shown in Table 3 below.

[table 3]


Test Example 3 Confirmation of S6K1 kinase activity inhibitory effect
The in vitro inhibitory activity of the compounds of the present invention on S6K1 kinase activity was measured using QSS Assist from Carna Biosciences^TM FP detection kit.
As for the measurement of the inhibitory activity of the compound, first, the test compound was diluted stepwise with dimethyl sulfene (DMSO). Next, S6K protein, matrix peptide (final concentration 100 nM), and magnesium chloride (final concentration 5 mM) were added to the kinase reaction buffer (20 mM HEPES (pH 7.4), 2 mM dithiothreitol, 0.01% Tween-20). ), ATP (final concentration: 25 μM) and the test compound DMSO solution (final concentration of DMSO: 5%), and incubated at 25 ° C. for 30 minutes to perform a kinase reaction. To this, the IMAP Progressive Binding Buffer A of Molecular Devices diluted 400 times was added to the IMAP Progressive Binding Reagent to stop the kinase reaction. After standing at room temperature for 120 minutes in the dark, the amount of phosphorylation reaction can be determined based on the polarization degree of fluorescence measured using PHERAstar (BMG LABTECH, excitation wavelength 485 nm, detection wavelength 520 nm). The concentration of the compound that inhibits the phosphorylation reaction is defined as the IC50 value (nM), and is shown in Table 4 below.

[Table 4]


Test Example 4 Cell proliferation inhibition test
An in vitro cell proliferation inhibition test on RKO cells (a human colorectal cancer cell line) was performed under the following conditions.
MEM medium (GIBCO, Cat #: 10370-) containing 10% FBS, 1 mM L-glutamine (GIBCO, Cat #: 25030) and 1 mM sodium pyruvate (GIBCO, Cat #: 11360) 088) cultured RKO cells (ATCC, Cat #: CRL-2577) at 2 × 10 per well³ (150 μl) were seeded into each well of a 96-well flat-bottomed microdisk (COSTAR, Cat #: 3904), and cultured in an incubator at 37 ° C. and 5% carbon dioxide for 1 day. The compound of the present invention diluted in the dimethyl sulfene stage, or only dimethyl sulfene, was added to a MEM medium containing 10% FBS, 1 mM L-glutamine and 1 mM sodium pyruvate. It was added to each well of the RKO cell culture plate in a manner of 50 μl per well so that the final concentration of the compound became 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, and 0 μM, respectively. In addition, a culture plate of RKO cells prepared separately was left at room temperature for 30 minutes, and 100 μl of the culture medium was removed. Then, 50 μl of CellTiter-Glo (registered trademark) 2.0 Assay (Promega, Cat #: G9242) was added to each well. . After being left in the dark for 10 minutes, the amount of luminescence from living cells derived from the wells when the compound was added was measured using a Multimode Plate Reader (PerkinElmer, EnSpire). Cells to which the compound was added or only dimethylphosphine were further cultured in an incubator at 37 ° C and 5% carbon dioxide for 3 days. After incubation, the cells were left at room temperature for 30 minutes, and 150 μl of the supernatant was removed from each well, leaving 50 μl of the cell culture solution. An equivalent amount of CellTiter-Glo (registered trademark) 2.0 Assay was added to 50 μl of the remaining cell culture solution. After being left in the dark for 10 minutes, the luminescence of living cells derived from each well was measured using a Multimode Plate Reader. The cell proliferation rate was calculated according to the following formula, and the concentration at which the cell proliferation rate was 50%, that is, the concentration of the compound of the present invention that inhibited cell proliferation by 50% (GI₅₀ Value (nM)).
Cell proliferation rate (%) = (T-C₀ ) / (C－C₀ ) × 100; T ≧ C₀ Situation
Cell proliferation rate (%) = (T-C₀ ) / C₀ × 100; T <C₀ Situation
C₀ : Luminous amount of pores when compound is added (count per second)
C: Luminescence of pores with only dimethylsulfine added (count per second)
T: luminescence of wells to which test compound is added (count per second)
As comparative compounds, Comparative Example A (WO2010 / 056563 (Example 31)) and Comparative Example B, which are known to have Akt inhibitory activity, were used below.
[Chemical 16]



Evaluation of GI of RKO cells by representative compounds and control compounds in the present invention₅₀ The results are shown in Table 5 below.

[table 5]


From this result, it is understood that the compound of the present invention has significantly higher cell proliferation inhibitory activity than the piperidine derivative known to have Akt inhibitory activity. In addition, it can be seen from the comparison between Compound 1 and Comparative Example B that R contains₃ , R₄ , R₅ And R₆ The substitution position of the amine side chain has a significant effect on the cell proliferation inhibitory activity. This difference in substitution position-based activity was previously completely unknown to the industry, and it is a surprising finding.
Test Example 5 Cell proliferation inhibition test
The in vitro cell proliferation inhibition test on HEC-6 cells (uterine body cancer cell lines) was performed under the following conditions.
HEC-6 cells (Health Science Research Resources Bank, cell number: JCRB1118) cultured in 15% FBS-containing MEM medium (GIBCO, Cat #: 10370) are seeded at 500 (20 μl) per well Each well of a 384-well flat-bottomed microplate (CORNING, Cat #: 3571) was cultured in an incubator at 37 ° C and 5% carbon dioxide for 1 day. The compound of the present invention diluted in the dimethyl sulfene stage, or only dimethyl sulfene was added to a MEM medium containing 15% FBS. Add 5 μl per well to each well of the above-mentioned HEC-6 cell culture plate, so that the final concentration of the compound becomes 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, 0 μM. Furthermore, a culture plate of HEC-6 cells prepared separately was left at room temperature for 30 minutes, and then 20 μl of CellTiter-Glo (registered trademark) 2.0 Assay (Promega, Cat #: G9243) was added to each well. After stirring for 10 minutes with a culture plate stirrer, it was left to stand in the dark for 30 minutes, and then the luminescence of living cells derived from each well was measured using a Multimode Plate Reader (PerkinElmer, EnVision). Cells to which the compound was added or only dimethylphosphine were further cultured in an incubator at 37 ° C and 5% carbon dioxide for 3 days. After incubation, it was left at room temperature for 30 minutes, and 25 μl of CellTiter-Glo (registered trademark) 2.0 Assay was added to each well. After stirring for 10 minutes with a culture plate stirrer, it was left to stand in the dark for 30 minutes, and then the luminescence of living cells derived from each well was measured using a Multimode Plate Reader. The cell proliferation rate was calculated according to the following formula, and the concentration at which the cell proliferation rate was 50%, that is, the concentration of the compound of the present invention that inhibited cell proliferation by 50% (GI₅₀ Value (μM)).
Cell proliferation rate (%) = (T-C₀ ) / (C－C₀ ) × 100; T ≧ C₀ Situation
Cell proliferation rate (%) = (T-C₀ ) / C₀ × 100; T <C₀ Situation
C₀ : Luminescence of pores when compound is added (count per second)
C: Luminescence of pores with only dimethylsulfine added (count per second)
T: luminescence of wells to which test compound is added (count per second)
As a control compound, Comparative Example A (WO2010 / 056563 (Example 31)) and Comparative Example B, which are known to have Akt inhibitory activity, were used.
Evaluation of the GI of the representative compound in the present invention on HEC-6 cells₅₀ The results are shown in Table 6.
[TABLE 6]


All publications, patents, and patent applications cited in this specification are incorporated directly into this specification by reference.

Claims (8)

A use of a compound represented by the following formula (I) or a salt thereof, which is used in the manufacture of a medicine for treating tumors, [Chem. 1] [In the formula, R ₁ is a monocyclic unsaturated heterocyclic group having 4 to 6 members having 1 to 3 hetero atoms selected from N, S, and O, which may have a substituent; R ₂ is a hydrogen atom, halogen Atom, hydroxyl, amine, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl; R ₃ , R ₄ And R _{5 are the} same or different and are a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group or a C3-C6 cycloalkyl group, or R ₃ and R ₄ together with the nitrogen atom to which they are bonded have a selective A monocyclic saturated heterocycle having 4 to 6 members of 1 to 3 heteroatoms in N, S, and O, and R ₅ is a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, or a C3-C6 Cycloalkyl, or R ₄ and R ₅ together with these bonded nitrogen atoms and adjacent carbon atoms form a single ring having 4 to 6 members of 1 to 3 heteroatoms selected from N, S, and O Saturated heterocycle of formula, and R ₃ is a hydrogen atom, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl; R ₆ is a hydrogen atom, C1-C6 alkyl, C1-C6 haloalkyl Or C3-C6 cycloalkyl; R ₇ and R _{8 are the} same or different, and are a hydrogen atom, a halogen atom, a hydroxyl group, an amine group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 haloalkyl group, C 2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, or R ₇ and R ₈ together with the carbon atoms to which they are bonded form a C3-C10 cycloalkyl; X ₁ is N, X ₂ CR ₉ , R ₉ is hydrogen atom, halogen atom, hydroxyl group, amine group, cyano group, nitro group, C1-C6 alkyl group, C1-C6 haloalkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, or C3 -C6 cycloalkyl; dotted line ( ) Is a single bond and X ₃ is CH]. As used in claim 1, wherein R ₁ is _one to three selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, and a C3-C10 cycloalkyl group. The substituent is a monocyclic unsaturated heterocyclic group having 4 to 6 members of 1 to 3 heteroatoms selected from N, S, and O. If the application of claim 1 or 2, R ₂ is a hydrogen atom or a halogen atom, R ₆ is a hydrogen atom, R ₇ is a C1-C6 alkyl group, R ₈ is a hydrogen atom or a C1-C6 alkyl group, and X ₁ is N R ₉ is a hydrogen atom or a halogen atom, and X ₂ is CH. As used in claim 2, wherein R ₁ is _one to three selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, and a C3-C10 cycloalkyl group. The substituents are furyl, thienyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridyl, or pyrazolyl. If the use of claim 1 or 2, wherein R ₃ , R ₄ and R _{5 are the} same or different, they are a hydrogen atom or a C1-C6 alkyl group, or R ₃ and R ₄ together with these bonded nitrogen atoms form A monocyclic saturated heterocyclic ring of 4 to 6 members of one nitrogen atom, and R ₅ is a hydrogen atom or a C1-C6 alkyl group, or R ₄ and R ₅ are bonded to the nitrogen atom and the adjacent carbon atom Together they form a monocyclic saturated heterocyclic ring having 4 to 6 members with one nitrogen atom, and R ₃ is a hydrogen atom or a C1-C6 alkyl group. As used in claim 1 or 2, wherein R ₁ is a pyridyl group having a halogen atom or a C1-C6 alkoxy group, a pyrazolyl group having a C1-C6 alkyl group and a C1-C6 haloalkyl group, and a C1-C6 halide Alkyl oxadiazolyl, or unsubstituted furyl, or thiazolyl, R ₂ , R _5, and R ₆ are hydrogen atoms, R ₃ is a hydrogen atom, and R ₄ is a C1-C6 alkyl group, or R ₃ and R ₄ together with these bonded nitrogen atoms form a monocyclic saturated heterocyclic ring having 4 to 6 members with 1 nitrogen atom, R ₇ is a C1-C6 alkyl group, and R ₈ is a hydrogen atom or C1- C6 alkyl, X ₁ is N and X ₂ is CH. As for the purpose of claim 6, wherein R ₁ is a pyrazolyl group having a C1-C6 alkyl group and a C1-C6 haloalkyl group, or an oxadiazolyl group having a C1-C6 haloalkyl group. For the use of claim 1 or 2, wherein the compound is selected from the group of compounds: 4- (4- (6- (5- (difluoromethyl) -1,3,4-fluorenediazol-2-yl) -3-((2- (pyrrolidin-1-yl) ethyl) Amine) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one; 4- (4- (3-((2- (third-butylamino) ethyl) amino) -6- (5- (trifluoromethyl) -1,3,4-fluorenediazole-2 -Yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one; and 4- (4- (3-((2- (third-butylamino) ethyl) amino) -6- (5- (difluoromethyl) -1,2,4-fluorenediazole-3 -Yl) pyridin-2-yl) piperidin-1-yl) -5,5-dimethyl-5H-pyrrolo [2,3-d] pyrimidin-6 (7H) -one.